Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?
© Sieber and Baumgrass; licensee BioMed Central Ltd. 2009
Received: 12 August 2009
Accepted: 27 October 2009
Published: 27 October 2009
The drugs cyclosporine A (CsA) and tacrolimus (FK506) revolutionized organ transplantation. Both compounds are still widely used in the clinic as well as for basic research, even though they have dramatic side effects and modulate other pathways than calcineurin-NFATc, too. To answer the major open question - whether the adverse side effects are secondary to the actions of the drugs on the calcineurin-NFATc pathway - alternative inhibitors were developed. Ideal inhibitors should discriminate between the inhibition of (i) calcineurin and peptidyl-prolyl cis-trans isomerases (PPIases; the matchmaker proteins of CsA and FK506), (ii) calcineurin and the other Ser/Thr protein phosphatases, and (iii) NFATc and other transcription factors. In this review we summarize the current knowledge about novel inhibitors, synthesized or identified in the last decades, and focus on their mode of action, specificity, and biological effects.
The Ser/Thr phosphatase calcineurin
Calcineurin, also named protein phosphatase 2B (PP2B), is a ubiquitously expressed cytosolic Ser/Thr protein phosphatase, highly conserved in eukaryotes. Calcineurin consists of two subunits - the enzymatic subunit A and the regulatory subunit B. The subunit A contains a calmodulin binding site and an autoinhibitory domain, which blocks the catalytic centre of the enzyme. Binding of Ca2+ ions and calmodulin to calcineurin leads to a change of conformation and a subsequent unmasking of the active centre. Thereby, calcineurin activity is coupled to cytosolic calcium levels, which is a unique property of calcineurin among the Ser/Thr protein phosphatases . Additionally, activity and localization of calcineurin is modulated by endogenous proteins, such as RCANs, Cabin1 or AKAP79. These regulatory proteins have been recently reviewed in detail [4, 5].
Calcineurin and NFATc
Calcineurin has the ability to dephosphorylate a broad range of proteins . Some of the most important substrates are the transcription factors of the NFATc (nuclear factor of activated T cells) family: NFATc1 to NFATc4 . NFATc regulates the expression of many genes by binding to DNA as dimers or in cooperation with other transcription factors. Among the regulated genes are cytokines such as IL-2, IL-4 and IFNγ or surface proteins such as CD40L and CD95L [8–10]. NFATc controls the expression of the endogenous calcineurin inhibitory protein RCAN1-4, thereby forming a negative feedback loop for the calcineurin-NFATc signalling .
Calcineurin seems to be the only protein phosphatase that dephosphorylates NFATc [12–14]. In resting T cells NFATc is highly phosphorylated and localized in the cytosol. Upon stimulation of T cells and subsequent calcium mobilization activated calcineurin dephosphorylates NFATc at 13 serine residues in the regulatory region , leading to its nuclear translocation by exposure of the nuclear localization sequences [16, 17]. Concerted rephosphorylation of NFATc leads to its translocation into cytosol and abrogation of NFATc transcriptional activity [18, 19].
NFATc is not only dephosphorylated by calcineurin but additionally interacts with calcineurin via two motifs binding at regions distinct from the catalytic centre of calcineurin. These motifs are named c alcin eurin b inding r egion (CNBR)1 and CNBR2 or PxIxIT and LxVP according to their consensus sequences, respectively . The PxIxIT region of NFATc binds even to inactive calcineurin and is responsible for basal NFATc-calcineurin interaction [21, 22]. The LxVP motif interacts just with activated calcineurin, because its binding site at calcineurin is masked by the autoinhibitory domain [23, 24]. Interaction of both NFATc motifs with calcineurin directs the regulatory region of NFATc into close vicinity to the active centre of calcineurin. This enables targeted dephosphorylation of specific NFATc serine residues by calcineurin. The PxIxIT calcineurin-binding motif of NFATc is shared by several other peptides and proteins binding to calcineurin. This motif may serve as a general calcineurin interface [25, 26].
Calcineurin not only modulates the activity of NFATc but also several other transcription factors such as NF-κB, AP-1, and Elk1 [27–33]. In addition, calcineurin interferes with other signalling pathways such as TGF-β-dependent signalling and the MAPK cascade [33, 34]. However, it is widely unknown, which components of these pathways are substrates or interaction partners of calcineurin and to which extent their dephosphorylation modulates the respective signalling.
In summary, calcineurin is unique in three aspects. First, it is the only Ca2+-dependent Ser/Thr protein phosphatase. Second, to date, only calcineurin is known to activate the NFATc transcription factors thereby controlling the expression of a broad range of genes. Third, the inhibition of calcineurin activity is so far the only effective therapeutic strategy to suppress the activation of memory CD4+ and CD8+ T cells [35, 36]. The "classical" drugs targeting calcineurin activity and subsequently inhibiting NFATc activation are cyclosporin A (CsA) and FK506 (tacrolimus). Inhibitors of calcineurin are indispensable for treatment of transplantation patients and represent a valuable tool for basic research.
CsA and FK506 - the classical calcineurin inhibitors
Cyclosporin A (CsA) and FK506 (tacrolimus) are widely used as effective immunosuppressants in the clinic, mainly in organ transplantation and dermatology [37–39]. Application of these compounds in basic research has substantially contributed to the elucidation of calcineurin-dependent signalling processes [40, 41].
The immunosuppressive properties of CsA were discovered 1976 in animal models . Since 1979 [43, 44] CsA is indispensible for transplantation medicine. In 1987, FK506 was described as an alternative to CsA , followed by its first clinical application in 1989 . Despite the widespread application of both compounds in the clinics their molecular mechanisms remained unclear until 1991. Then, Liu et al. identified calcineurin as the common target of both compounds if and only if they are complexed with the respective endogenous partners, the immunophilins. They showed that neither the isolated immunophilins nor the immunosuppressants alone but only immobilized immunophilin/immunosuppressant complexes are able to pull down the calcineurin/calmodulin protein from cellular extracts. These experiments clearly demonstrated that CsA and FK506 are not active calcineurin inhibitors by themselves but need binding to their endogenous matchmaker proteins to be activated in a gain of function mechanism [47, 48]. Immunophilins, belonging to the class of peptidyl-prolyl cis-trans isomerases (PPIases), are involved in de novo protein folding and many other cellular functions [49, 50]. Binding of CsA or FK506 to their respective major intracellular acceptor proteins cyclophilin A (CypA) and FK506 binding protein 12 (FKBP12) inhibits their PPIase activity. These CsA- and FK506-PPIase-complexes are noncompetitive inhibitors of calcineurin. Thereby, they severely limit the access of protein substrates to the active centre of calcineurin [51–54] and mask the docking site for the NFATc LxVP motif at calcineurin . Thus, they inhibit the dephosphorylation of physiological targets of calcineurin. However, small molecular substrates like p-nitrophenyl phosphate (pNPP) are still being dephosphorylated [55, 56]. The activity of other Ser/Thr protein phosphatases such as PP1, PP2A or PP2C is not affected by CsA- or FK506-complexes.
Although CsA and FK506 share a similar mode of action, they belong to different chemical classes. CsA is a fungal cyclic undecapeptide , whereas the bacterial FK506 belongs to the chemical class of macrolides [58, 59].
Application of CsA and FK506 inhibits the T cell receptor (TCR)-dependent activation, proliferation, and differentiation of T cells. Both compounds inhibit the activation of NFATc and p65/NF-κB [60, 61]. However, NF-κB regulated gene transcription is not completely blocked, due to additional, calcineurin-independent activation pathways for NF-κB . Other cellular processes, such as CREB transcripitional activity  and proteasomal degradation of proteins [64, 65], are modulated by CsA or FK506 treatment, too.
So far, CsA and FK506 are the only drugs suppressing not only the activation of naïve and effector TH cells, but in addition of memory TH cells. Therefore, the application of these drugs is crucial in particular for transplantation patients with high numbers of alloreactive memory/effector T cells, which cannot be controlled with calcineurin-inhibitor-free treatment protocols [35, 66]. However, their use in clinical routine is often limited by severe side effects such as nephro- and neurotoxicity . It is not known so far whether these side effects are mainly due to inhibition of calcineurin- or immunophilin-dependent mechanisms. Furthermore, it is not clear whether the modulation of the calcineurin-NFATc pathway or of other pathways and transcription factors cause the adverse side effects.
To dissect the different actions of CsA or FK506, alternative inhibitors should ideally discriminate not only between the inhibition of calcineurin and the other Ser/Thr protein phosphatases but in addition between the inhibition of calcineurin and PPIases as well as of NFATc and other substrates of calcineurin. Compounds having these properties would be more specific than CsA and FK506 and might cause fewer side effects in clinical applications. In basic research such compounds would help to identify and characterize different targets of calcineurin .
Small molecular inhibitors
Low molecular weight inhibitors of calcineurin-NFATc signalling
Mode of action
General protein phosphatase inhibitors inhibiting also calcineurin (CaN)
binds to the active centre of PP1, PP2A, CaN
11,5 μM** a
Tatlock JH 1997 
binds covalently to the active centre of PP1, PP2A, CaN
Born TL 1995 
binds to the active centre of PP1, PP2A, CaN
Steward SG 2007 
binds to the active centre of PP1, PP2A, CaN
Bialojan C 1988 
bind possibly to the active centre of PP1, PP2A, CaN
21 - 62 μMb
Martin BL 1998 
Inhibitors of calcineurin-dependent signalling - CsA, FK506 and derivatives
complex blocks substrate access to the active centre of CaN
Fruman DA 1992 
complex blocks substrate access to the active centre of CaN
Aspeslet L 2001 
blocks substrate access to CaN independent of CypA
Baumgrass R 2004 
complex blocks substrate access to the active centre of CaN
Fruman DA 1992 
complex blocks substrate access to the active centre of CaN
Sinclair PJ 1996 
complex blocks substrate access to the active centre of CaN
Grassberger M 1999 
Inhibitors of calcineurin-dependent signalling - alternative inhibitory compounds
binds to the active centre of CaN
Baba Y 2003 
inhibits NFATc-DNA binding
Caballero FJ 2007 
inhibits of NFATc dephosphorylation in cells
Trevillyan JM 2001 
decreases Ca2+ influx into cytosol
Ishikawa J 2003 
inhibits enzymatic activity of CaN
Brill GM 1996 
disrupts CaN-NFATc binding
Mulero C 2009 
inhibits enzymatic activity of CaN
Baumgrass R 2001 
0.5 μM* f
Roehrl MH 2004 
disturb CaN-NFATc complex formation by covalent binding to CaN
0.12 μM* f
Roehrl MH 2004 
0.8 μM* f
Roehrl MH 2004 
inhibits enzymatic activity of CaN
Wang H 2008 
inhibits enzymatic activity of CaN
Klettner A 2001 
disturbs CaN-NFATc binding in cells
Sieber M 2007 
inhibits enzymatic activity of CaN
Gualberto A 1998 
enhances rephosphorylation and nuclear export of NFATc
Proksch P 2005 
enhances nuclear export of NFATc
Lindstedt R 2009 
inhibits CaM-dependent activity of CaN
Humar M 2004 
inhibits binding of CaM to CaN
Aussel C 1995 
inhibits CaN-dependent NFATc transactivation
Vega Lde L 2005 
inhibits NFATc binding to DNA
Román J 2007 
alters NFATc binding to DNA
Baine Y 1995 
Inhibitors of calcineurin-dependent signalling - unknown mode of action
Caffeic Acid Phenethyl Ester
Marquez N 2003 
Jung EJ 2009 
Burres NS 1995 
Kuromitsu S 1997 
< 5 μMg
Lee SI 2008 
Marquez N 2004 
Quinolone alkaloid compounds 1 and 3
Jin HZ 2004 
Cai XF 2004 
oleanane triterpenoid compound 3
Dat NT 2004 
Lee IS 2003 
CsA is a cyclic undecapeptide causing CypA and calcineurin inhibition via different parts of the molecule. CsA residues 2-9 are responsible for CypA binding, while CsA residues 4-7 are involved in calcineurin binding.
Modifications in position 3 , position 6 [70, 71] or position 8  resulted in some CsA derivatives, such as [( S )α-methylthiosarcosine 3 ]-CsA, [N-Methyl-Ala 6 ]-CsA and [D-Diaminopropyl 8 ]-CsA, which bind to CypA but are not able to inhibit calcineurin's activity, neither in their uncomplexed form nor in the complex with CypA.
Several other CsA derivatives substituted in position 3, e.g. [( R )α-Methylsarcosine 3 ]CsA and [Dimethylaminoethylthiosarcosine 3 ]CsA have been found to inhibit calcineurin without prior formation of a complex with cyclophilin 18 or inhibition of its isomerase activity. However, both compounds show affinity towards CypA and can therefore not be considered monospecific .
Modifications of CsA in the position 1 change the affinity of the derivatives towards CypA. The derivative [MeBm 2 t] 1 -CsA has a lower binding affinity than CsA , but the binary complex retains the immunosuppressive capacity. The derivative ISA247 (voclosporin) has a higher affinity to CypA than CsA [75, 76] and has the potential to be administered in lower concentrations. Therefore it might be less toxic than CsA and is under investigation in phase II and III trials for psoriasis patients [77, 78].
FK506 has several derivatives with the same mode of action. Among them are the immunosuppressive compounds FK520 (ascomycin) and pimecrolimus. Other FK506 derivatives are monospecific for FKBP12 binding and inhibition, such as L-685,818 (FK506BD)  and V-10,367 . However, so far there are no FK506 derivatives with monospecific action on calcineurin.
Several of the immunosuppressive derivatives have been characterized in detail.
FK520  is a naturally occurring FK506 derivative containing an ethyl group in the position 21 and is used as an immunosuppressant in vitro and in rodent models. Several semisynthetic immunosuppressive compounds are derived from FK520. Pimecrolimus (SDZ AM 981, 33-epi-chloro-33-desoxy-ascomycin) , is routinely used in the topical treatment of inflammatory skin diseases. It is more lipophilic than FK506 and therefore more affine to the skin, has low systemic effects, and does not induce skin atrophy, in contrast to topical steroids. The derivative L-732,531 (32-O-(1-hydroxyethylindol-5-yl)-ascomycin) binds poorly to FKBP12, but the stability of the L-732,531-FKBP12-calcineurin-complex is much higher compared to the complex with FK506 . This might be the reason that L-732,531 has less severe side effects in a murine transplant model .
Interestingly, FK506 and its related, naturally occurring immunosuppressive compound rapamycin (sirolimus) share the FKBP-binding domain but differ in their effector domains . Rapamycin/FKBP12 does not bind to calcineurin , but exerts its immunosuppressive and antiproliferative effects via inhibition of the mTOR/Akt signalling. This signalling node is part of costimulatory and IL-2 receptor signalling pathways . Rapamycin is often used in clinical routine in prolonged treatment of transplantation patients after initial CsA or FK506 application. Rapamycin suppresses posttransplantational malignant neoplasia due to its antiproliferative properties .
Inhibitors acting on the calcineurin molecule
The catalytic centre of calcineurin (PP2B) shares the structure and conformation with other Ser/Thr protein phosphatases, namely PP1 and PP2A. Therefore, several inhibitors targeting the active centre of calcineurin additionally inhibit these protein phosphatases, too. Among them are 4-(fluoromethyl)phenyl phosphate (FMPP) , tyrphostins  and norcantharidin . However, some inhibitors, such as okadaic acid or endothall, show different affinities towards different phosphatases. By using selected concentration ranges of these inhibitors it is possible to inhibit mainly PP1 and PP2A, but calcineurin to a lower degree. Okadaic acid inhibits PP1 and PP2A in nanomolar, but calcineurin in micromolar concentrations . Pyrethroid insecticides do not possess any ability to inhibit calcineurin [92, 93], contrary to an earlier report.
The following compounds (Table 1; see additional file 1 for IUPAC names or chemical structures) inhibit calcineurin specifically among the Ser/Thr protein phosphatases. They might act mainly as noncompetitive inhibitors, such as CsA and FK506, but in contrast to them they do not need a matchmaker protein.
Kaempferol, a natural flavonol, inhibits the phosphatase activity of purified calcineurin against pNPP and RII phosphopeptide. Kaempferol binds to the catalytic domain of calcineurin A and acts independently of any matchmaker protein. Protein phosphatase 1 and alkaline phosphatase activity are not inhibited by this compound. Kaempferol suppresses IL-2 gene expression in Jurkat T cells [94, 95]. Surprisingly, it also inhibits the calcineurin-independent TNFα-induced NF-κB activation in HEK293 cells .
Barbiturates such as thiopental, pentobarbital, thiamylal and secobarbital are inhibitors of the phosphatase activity of calcineurin . They inhibit the calmodulin-mediated dephosphorylation of the RII phosphopeptide  in enzymatic assays, as well as NFATc dephosphorylation, NFATc nuclear translocation and cytokine production in T cells. These effects do not depend on binding of the barbiturates to their GABA receptor and its subsequent signalling. Additionally, barbiturates inhibit AP-1 activation independently of calcineurin . Thiopental suppresses NF-κB activation via unknown mechanisms . In lymphocytes, thiopental decreases antigen- but not mitogen-induced proliferation, IL-2 expression and IFNγ expression .
1,5-dibenzoyloxymethyl-norcantharidin is a derivative of norcantharidine [101, 102]. Among other compounds, it was synthesized according to a computational interaction model of norcantharidin carboxylate with the catalytic centre of calcineurin. It has been selected by screening for specific binding to calcineurin, but not to PP1 and PP2A. 1,5-dibenzoyloxymethyl-norcantharidin inhibits the dephosphorylation of pNPP and the RII phosphopeptide by calcineurin. However, no data about inhibition of protein dephosphorylation in cell-free assays or in cells have been reported for this compound.
Gossypol, a cell permeable polyphenole identified in cotton plants, inhibits noncompetitively the enzymatic activity of calcineurin but of none of the other Ser/Thr protein phosphatases. The inhibition of pNPP and RII phosphopeptide dephosphorylation is reversible and is independent of immunophilins or other matchmaker proteins. Gossypol inhibits the nuclear translocation of NFATc in activated T cells. The reported effect of gossypol on calcineurin-calmodulin interaction  cannot account for these specific effects, as gossypol only partially prevents the binding of calmodulin to calcineurin and just at very low concentrations of calmodulin. Gossypol shows immunosuppressive effects in mice  and inhibitory effects on growth, cell signalling and development in Dictyostelium cells. These effects are specific for calcineurin as they can be diminished by calcineurin overexpression . However, gossypol has been reported to additionally inactivate other enzymes than calcineurin such as dehydrogenases , phospholipase A2  and topoisomerase II .
Lie120, a thiazole derivative, inhibits the enzymatic activity of calcineurin but not the PPIase activity of FKBPs or cyclophilins. Dephosphorylation of pNPP and RII phosphopeptide is inhibited by Lie120 in cell-free assays. In neuronal cell lines it prevents the FK506-sensitive H2O2-triggered activation of JNK. However, Lie 120 is toxic at concentrations higher than 5 μM .
PD 144795, a benzothiophene derivative, blocks the enzymatic activity of calcineurin in cell lysates. In Jurkat T cells transfected with an HIV-1 LTR fragment, PD 144795 inhibits the calcineurin-dependent binding of p53 and NF-κB to the HIV promoter element. These inhibitory effects are abolished by overexpression of calcineurin .
Dibefurin, a fungal phenolic compound, inhibits the enzymatic activity of calcineurin against the small molecular substrate 4-methylumbelliferyl phosphate. Furthermore, it shows suppressive effects in both assays, mixed lymphocyte reaction (MLR) and lymphocyte cytotoxicity analysis .
Compounds inhibiting the enzymatic activity of calcineurin are supposed to block the dephosphorylation of all protein substrates. Therefore, only compounds targeting specific calcineurin-substrate interactions but not the general phosphatase activity of calcineurin might be able to dissect the action of calcineurin on different substrates. Recently, different efforts were made to identify such compounds, interfering specifically with calcineurin-NFATc interactions in T cells.
Dipyridamole, a drug clinically used for stroke treatment, is suggested to affect the interaction of NFATc with calcineurin, because it competes with fluorescence-labelled RCAN1-CIC peptide (see below) for binding to calcineurin. Dipyridamole does not interfere with the phosphatase activity of calcineurin on RII phosphopeptide in cell-free assays. It suppresses ionomycin-induced NFATc2 nuclear translocation in Jurkat T and U-2 osteosarcoma cell lines, and blocks subsequently NFATc-dependent reporter gene and cytokine expression . Dipyridamole inhibits TNFα production in activated PBMC .
NCI3, a pyrazolopyrimidine derivative, does not influence the enzymatic activity of calcineurin in cell-free systems. However, NCI3 inhibits NFATc dephosphorylation and nuclear translocation, IL-2 secretion and cell proliferation upon stimulation of Jurkat or primary human T cells. NFATc-dependent reporter gene expression is more sensitive to NCI3 than NF-κB, whereas AP-1-dependent transcription is not influenced. These effects are diminished by calcineurin overexpression. An effect of NCI3 on the calcineurin-substrate interface is postulated as it partially displaces the VIVIT peptide, an oligopeptide derived from the PxIxIT-calcineurin binding motif of NFATc (see below) .
INCA compounds are a group of chemically unrelated substances selected in a screening for inhibition of NFATc-calcineurin interaction. INCA-1, 2 and 6 bind covalently but reversibly to calcineurin at the residue Cys266. Subsequently, steric changes mask the binding site for NFATc and VIVIT peptide. INCA-2, but not INCA-6, inhibits the enzymatic activity of calcineurin. INCA-6 inhibits the dephosphorylation of NFATc and its nuclear import in ionomycin-stimulated Cl.7W2 murine T cell line and, consequently, the expression of IFNγ and TNFα. However, general cytotoxicity has been reported for all INCA compounds, ruling out their use in primary cells [114, 115].
Inhibitors not acting directly on the calcineurin molecule
Inhibitors of calcineurin-NFATc signalling may not only act on calcineurin itself, but also up- or downstream of the calcineurin-NFATc interaction or dephosphorylation processes. Among the possibilities are effects of compounds on calcium mobilization, on the nuclear translocation of NFATc or on NFATc-DNA-binding (Figure 2). Inhibitors acting downstream of calcineurin activation might be more specific to suppress just NFATc activation than CsA or FK506 complexes.
BTP1 and BTP3 (compounds 1 and 2 in Djuric et al.) are supposed to interfere with calcineurin-dependent NFATc activation, because calcineurin activity against RII phosphopeptide and phosphorylated Elk1 is not inhibited in enzyme assays and in cell lysates. BTP1 and BTP3 diminish activation-dependent NFATc dephosphorylation, its nuclear translocation in primary T cells and cell lines as well as subsequent cytokine production and cell proliferation. It is assumed that NF-κB or AP-1 activation are not affected by BTP1 and BTP3 .
BTP2 (compound 3 in Djuric et al., alternative name YM-58483) dose-dependently enhances TRPM4, a Ca2+-activated nonselective cation channel. Thereby, BTP2 decreases CRAC-channel-dependent Ca2+ influx due to depolarization of lymphocyte cell membranes. Subsequently, the activation of calcineurin is diminished, leading to a reduced NFATc-driven promoter activity and IL-2 production in Jurkat T cells. AP-1-driven promoter activity is not influenced. BTP2 also inhibits the proliferation and Ca2+-dependent cytokine production in stimulated human CD4+ T cells [119–121] and the expression of IL-4 and IL-5 in an antigen-stimulated murine TH2 T cell clone. In vivo studies show an inhibition of antigen-induced airway-inflammation , of donor anti-host cytotoxic T lymphocyte activity and IFNγ production in graft versus host disease, and of delayed-type hypersensitivity response in mice . Inhibition of Ca2+-dependent functional responses of human neutrophils and granulocyte-differentiated HL60 cell line was also observed . However, it is unclear to which extent these observed effects are caused by inhibition of calcineurin, because other Ca2+-dependent processes are suppressed, too. In particular, the activation of the calmodulin-dependent kinases (CaMK) plays an important role in T cell activation and inflammatory responses.
BTP A-285222 (compound 19 in Djuric et al.) has immunosuppressive effects in an animal model but exhibits severe side effects, such as neurotoxicity. The molecular mode of action of BTP A-285222 is not known, nevertheless many effects on different cell types are observed. It was found that cytokine production of T cells is reduced by 80% in BTP A-285222-treated mice , that agonist-induced NFATc3-dependent IL-6 production is inhibited in myometrial arteries and that proliferation of isolated vascular smooth muscle cells is impaired [126, 127].
ST1959, a 3,5-diaryl-s-triazole derivative which is also named DL111-IT/contragestazol, inhibits T cell activation, proliferation and cytokine production by enhancing the nuclear export of NFATc2. NFATc2 de- and rephosphorylation are not influenced. NF-κB- and AP-1-dependent gene transcription are reported to be not affected . The compound shows immunosuppressive effects in several animal models of autoimmune diseases, such as colitis and host versus graft disease [129, 130].
AM404, a product of the acetaminophen (paracetamol) catabolism , inhibits NFATc2-DNA binding and transcriptional activity in Jurkat T cells, but not in cell lysates. It is postulated that AM404 inhibits the nuclear translocation of dephosphorylated NFATc. AM404 does not inhibit Ca2+ influx, disturbs only slightly the dephosphorylation of NFATc2 in cells and does presumably not interfere with the signalling pathways leading to NF-κB or AP-1 activation. However, AM404 suppresses IL-2 and TNFα transcription, T cell proliferation and cytokine release in Jurkat T cells after αCD3/28 stimulation .
UR-1505 is a pentafluoropropoxy derivative of salicylic acid . It blocks the binding of NFATc to DNA upon ionomycin stimulation but has no effect on the nuclear translocation of NFATc. Therefore, UR-1505 effects are not due to NFATc-export inhibition or enhanced re-phosphorylation. The activation of NF-κB and AP-1 seems to be not affected. UR-1505 inhibits αCD3/CD28-induced, but not JAK/STAT-induced T cell proliferation and IL-5 as well as IFNγ expression. UR-1505 shows anti-inflammatory properties in rat colitis models . Triflusal, another salicylic acid derivative, inhibits not only NFATc-DNA complex formation, but additionally NF-κB activation .
Rocaglamide derivatives Roc-1, 2 and 3 inhibit the activation-induced NFATc1 translocation into the nucleus. It is supposed that elevated kinase activities of p38 MAPK and JNK by Roc-1, 2 and 3 cause an increased NFATc re-phosphorylation. This inactivation of NFATc leads to a reduced expression of IL-2, IL-4, IFNγ and TNFα. The nuclear localization of c-Jun, a potential subunit of AP-1, is also inhibited. Surprisingly, only NFATc- but not AP1- or NF-κB-dependent reporter gene transcription is suppressed by the inhibitors in the selected concentration range (up to 100 nM) .
Tropisetron, an antagonist of the serotonin receptor, inhibits NFATc-dependent signalling caused by overexpression of the constitutively active calcineurin construct ΔCaM-AI . Therefore, a target at or downstream of calcineurin activity was suggested. Tropisetron inhibits the transcriptional activities of NFATc, NF-κB and AP-1 in PMA/ionomycin-, but not TNFα-stimulated Jurkat T cells. Tropisetron suppresses the phosphorylation of p38 MAPK and JNK but not the phosphorylation of ERK 1 and 2. It inhibits IL-2 production in primary T cells upon SEB stimulation . Tropisetron ameliorates acetic-acid-induced colitis in rats .
Venkatesh et al. selected 14 compounds in a screening of a library with 16,000 substances for inhibitors of GFP-NFATc3 nuclear translocation in HeLa cells. Most of them interfered with calcium mobilization and therefore calcineurin activation .
WIN 53071 alters NFATc-DNA complex formation in intact cells but not in cell-free binding assays. It does not inhibit the enzymatic activity of calcineurin against RII phosphopeptide. WIN 53071 inhibits Ca2+-dependent IL-2 expression in primary human lymphocytes, MLR and NFATc-driven reporter gene expression .
Trifluoperazine binds to calmodulin and inhibits its interaction with calcineurin . Therefore, trifluoperazine inhibits calcineurin activation and suppresses the dephosphorylation of RII phosphopeptide in cell lysates  and IL-2 expression of αCD3/PMA-activated Jurkat T cells. Due to its mode of action, also other calmodulin-dependent but calcineurin-independent processes are modulated, such as phosphatidylserine synthesis .
Inhibitors with unknown mode of action
Several compounds, belonging to different chemical classes, were found to inhibit NFATc-dependent gene expression and other NFATc-mediated cellular effects. However, the underlying molecular mechanisms of the compounds listed in this chapter were not elucidated in detail by the respective authors.
KRM-III inhibits NFATc-, but not NF-κB-dependent reporter gene expression in PMA/ionomycin stimulated Jurkat T cells. KRM-III diminishes the proliferation of TCR-stimulated murine T cells and MLR. Upon oral application to mice, KRM-III reduces the IL-2 levels in blood after αCD3-injection, and diminishes delayed type hypersensitivity responses and MOG-induced experimental autoimmune encephalomyelitis .
Caffeic Acid Phenethyl Ester (CAPE), a phenolic compound derived from honey bee propolis, inhibits IL-2 promoter activity and cytokine synthesis, NF-κB binding to DNA in PMA-stimulated Jurkat cells (but not IκBα degradation), NFATc dephosphorylation after PMA/ionomycin stimulation, and the DNA binding of a pGal4-NFATc2(1-415) fusion protein in cells. CAPE inhibits not only the percentage of cells expressing the activation markers CD25, CD69, and ICAM-1 at the cell surface but also the relative intensity of fluorescence in the positive cell population . It is a potent inhibitor of antigen- and mitogen-induced T-cell proliferation, cytokine production , and NF-κB activation . The precise mode of action of CAPE remains unclear.
YM-53792 suppresses NFATc-, but not AP-1- and NF-κB-driven promoter activities and the formation of NFATc-DNA complexes in stimulated Jurkat cells. YM-53792 inhibits IL-2 gene promoter activity and the expression of IL-2, IL-4 and IL-5 in stimulated human peripheral blood mononuclear cells. It was assumed that YM-53792 specifically inhibits the calcineurin-NFATc pathway, but the molecular mechanism is not elucidated .
Quinazolinediones and pyrrolopyrimidinediones, selected by screening of a compound library, inhibit NFATc-dependent reporter gene transcription in Jurkat cells . No further examination of their mode of action has been reported. Recent data suggest that the inhibitory effect of quinazolinediones such as WIN 61058  is independent of calcineurin but due to inhibition of the monocarboxylate transporter MCT1, which is crucial in the export of catabolic lactate from activated blastic T cells .
NFAT-68 and NFAT-133 are no proteins but in fact fungal aromatic compounds. They do not interfere with calcineurin phosphatase activity against 4-methylumbelliferyl phosphate, but inhibit NFATc-driven reporter gene transcription, MLR and lymphocyte toxicity .
Many traditional medical plants, parts of plants or specific preparations from them often have anti-inflammatory properties. To identify the responsible natural ingredients and to search for novel calcineurin-NFATc-pathway inhibitors, different libraries were recently screened for inhibitors of NFATc-dependent reporter gene expression. Unfortunately, most of the selected compounds were not further characterized concerning their mode of action and their effects on the inhibition of other transcription factors and pathways.
Punicalagin, isolated from the fruit of Punica granatum, inhibits NFATc nuclear translocation and DNA binding. It diminishes αCD3/28-induced IL-2 production of CD4+ T cells and shows slight suppression of MLR. Immunosuppressive effects of punicalagin were observed in a PMA-induced edema mouse model .
Imperatorin isolated from Oppopanax chironium(L.), a furanocumarin, inhibits both NFATc transcriptional and DNA-binding activities. It blocks the expression of the reporter gene luciferase controlled by NFATc- or IL-2-dependent promoter region, but not the expression under control of an NF-κB- or AP-1-dependent promoter. Imperatorin suppresses the proliferation of SEB-stimulated T cells .
Quinolone alkaloids from the Evodia rutaecarpa fruit inhibit NFATc- and NF-κB-dependent reporter gene expression in Jurkat T cells. Several of these alkaloids suppress NFATc signalling stronger than NF-κB without affecting the viability of the Jurkat T cell line .
Several compounds, extracted from of Asian plants, inhibit NFATc-dependent reporter gene expression: phenolic constituents 2 and 3 of Desmos chinensis , gymnasterkoreayne G, a polyacetylene isolated from the leaves of Gymnaster koraiensis , compound 1 from Ribes fasciculatum var. chinense , Impressic acid , lignans , and diterpenoids , contained in Acanthopanax koreanum root, oleanane triterpenoid compound 3, contained in the fruits of Liquidambar formosana, , as well as gomisin N and schisandrol A, lignans from Schisandra chinensis .
Inhibitory peptides and proteins from pathogens
Peptides and proteins inhibiting calcineurin-NFATc signalling
Mode of action
Perrino BA 1999 
mask the active centre of CaN
Sagoo JK 1996 
mNFATc2106-121 - SPRIEIT
Aramburu J 1998 
block CaN-NFATc interaction
0.5 μM* k
< 1 μMl
Roehrl MH 2004 
Aramburu J 1999 
blocks CaN-NFATc interaction
Dell'Acqua ML 2002 
60 nM* k
Chan B 2005 
RCAN1-4141-197 - exon7
block CaN-NFATc interaction
70 nM* k
Chan B 2005 
RCAN1-4143-163 - CIC peptide
1.25 μM* k
Mulero MC 2009 
blocks CaN-NFATc interaction and modulates enzymatic activity of CaN
Rodriguez A 2009 
RCAN1-495-118 - SP repeat peptide
masks the active centre of CaN
91.5 μM** a
Vega RB 2002 
inhibits translocation of NFATc
Gebert B 2003 
Miskin JE 1998 
block CaN-NFATc interaction
Miskin JE 2000 
AID fragments, derived from the autoinhibitory domain of the calcineurin A subunit were the first examined inhibitory peptides for calcineurin. These peptides, containing the residues 424-521 (AID 424-521 ), are potent inhibitors of the phosphatase activity by blocking the access of protein substrates to the catalytic centre of calcineurin . A peptide spanning the residues 457-482 (AID 457-482 ) of calcineurin represents the core inhibitory motif [165, 166]. This peptide is already able to suppress the dephosphorylation of the RII phosphopeptide in phosphatase assays. However, additional autoinhibitory elements are present within the calcineurin region 420-457. Therefore, the peptides containing the extended AID region AID420-511 and AID328-511 were three- to fourfold more potent to inhibit RII phosphopeptide dephosphorylation compared to the AID457-482 peptide . The 11R-AID457-482 peptide, containing eleven arginine residues, is reported to be indeed cell-permeable for selected cell types. It inhibits apoptosis of excitatory neurons  and caerulein-induced zymogen activation in pancreatic acinar cells .
PxIxIT peptides are derived from the conserved calcineurin-docking motif PxIxIT found in NFATc and other proteins . Peptides or protein fragments containing the PxIxIT element compete with NFATc for binding to calcineurin and impair thereby the binding and dephosphorylation of NFATc1, c2 and c4 in cell-free enzyme assays. In cells overexpressing PxIxIT peptides, the phosphatase activity of calcineurin and therefore the dephosphorylation of other substrates are not impaired [21–23, 25].
The VIVIT 16 mer oligopeptide, designed by selective amino acid exchange, possesses 25 times higher efficiency to inhibit NFATc dephosphorylation compared to the original NFATc2 16 mer SPRIEIT peptide . Overexpression of GFP-VIVIT fusion protein in Jurkat T cells inhibits NFATc- but not NF-κB-dependent reporter gene expression. Therefore, the VIVIT peptide is more selective than CsA and FK506 complexes which inhibit the activation of both transcription factors. 11R-VIVIT peptide is claimed to be cell-permeable in selected cell types , but there are contrary experimental experiences.
A peptide derived from the calcineurin-anchoring protein AKAP79 containing the PIAIIIT motif (AKAP79 330-357 ) binds to purified calcineurin. In contrast to other PxIxIT peptides, this motif inhibits the phosphatase activity against the RII phosphopeptide. Overexpression of AKAP79330-357 in HEK293 cells antagonizes the interaction between AKAP79 and calcineurin .
The endogenous inhibitory protein CABIN1 contains a conserved PEITVT motif. A peptide spanning the residues 2078-2115 of rat CABIN1 binds to calcineurin , and human CABIN1 2143-2220 overexpression in Jurkat T cells inhibits NFATc dephosphorylation and NFAT-dependent luciferase expression . Both fragments overlap at the KFPPEITVTPP sequence. Therefore, this motif is assumed to participate in the CABIN1-calcineurin interaction.
RCAN1, an endogenous modulator of calcineurin activity (also named DSCR1 or calcipressin1), is expressed in several splice variants which differ in their N termini but share an identical C terminus. In this review, the amino acid designation has been adapted from the splice variant RCAN1-4 , although several cited publications use the designation of the splice variant 1-1. RCAN1-exon7 (RCAN1-4 residues 141-197), containing the C-terminus, binds to full-length calcineurin and to a catalytic core fragment of calcineurin as well as full-length RCAN1. Both, RCAN1-exon7 and full-length RCAN1, inhibit competitively the dephosphorylation of pNPP in enzyme assays and the calcineurin-mediated nuclear translocation of NFATc3 in the BHK cell line after their overexpression . Initially, the PKIIQT motif in this region (RCAN1-4181-186) was considered to mimic the NFATc PxIxIT motif and to inhibit NFATc-calcineurin interaction, but a peptide spanning the residues 178-191 did not compete with VIVIT peptide for binding to calcineurin. Recent experiments revealed that the RCAN1-4 136-163 fragment contains a region named calcineurin-inhibitor calcipressin 1 (CIC) motif, which is displaced from calcineurin by the VIVIT peptide . The RCAN1-4 143-163 CIC fragment binds to calcineurin A with high affinity, competes with the binding of VIVIT peptide, and inhibits NFATc2 nuclear translocation as well as NFATc-dependent reporter gene expression in transfected COS-7 cells. Importantly, this fragment does not interfere with the phosphatase activity of calcineurin towards RII phosphopeptide and homologous regions are found in the related proteins RCAN2 (residues 147-167) and RCAN3 (residues 183-203) . This fragment contains the "true" PxIxIT motif of RCANs - PSVVVH, which binds to the same hydrophobic pocket of calcineurin as the VIVIT peptide. Therefore, the PSVVVH peptide (RCAN1-4 149-166 ) competes with the regulatory region of NFATc2 or GST-CABIN1 for binding to calcineurin .
A peptide derived from the C-terminus of the yeast RCAN homologue Rcn2 (Rcn2 252-265 ), containing the PSITVN motif, is able to compete with the VIVIT peptide for binding to human calcineurin, too. Consequently, deletion of this motif in Rcn2 abolishes its inhibition of calcineurin signalling in yeast .
The African Swine Fever Virus protein A238L contains a similar motif the PKIIITG motif (see below).
LxVP peptides are derived from the conserved calcineurin-docking NFATc motif LxVP and compete with NFATc for the binding to activated calcineurin. The NFATc isoforms differ in the affinity of their LxVP motifs towards calcineurin .
Pep3 is derived from the CNBR2 of NFATc3 (residues 321-406 of murine NFATc3). This 16-amino acid oligopeptide (mNFATc3385-400) contains the LxVP motif, binds to purified and cellular calcineurin and competes with GST-CNBR2 for binding to calcineurin. Retroviral overexpression of Flag-Pep3 in the murine D10G4.1 TH2 cell line impaired the expression of IL-5, IL-6 and IL-13 and the nuclear translocation of NFATc3 after PMA/calcium ionophore stimulation. NFATc3, but not NFATc2 and NF-κB activation is affected by Pep3 .
The LxVPc1 peptide, spanning the 15 amino acids of human NFATc1 371-385, disrupts calcineurin-NFATc1 and c2 binding. GST-LxVPc1 binds to calcineurin more efficiently than any of the PxIxIT motifs of NFATc1 to c4. The GST-LxVPc2 fusion peptide from NFATc2 was unable to bind to calcineurin under the same conditions. The LxVPc1 peptide inhibits calcineurin phosphatase activity on the RII phosphopeptide and increases the phosphatase activity on pNPP. Overexpression of GFP-LxVPc1 fusion protein in HeLa cells inhibits NFATc2 dephosphorylation and nuclear translocation upon ionophore treatment; in Jurkat T cells it inhibits NFATc2 dephosphorylation and the expression of luciferase under control of the IL-2 or RCAN1-4 promoter upon PMA/ionophore stimulation [23, 24].
Protein fragments based on other motifs were derived from CABIN1 and RCAN1. The protein fragment CABIN1 700-901 inhibits the dephosphorylation of the RII phosphopeptide by calcineurin in a noncompetitive manner. Overexpression of CABIN1700-901 in HEK293 cells coexpressing constitutively active calcineurin inhibits the dephosphorylation of NFATc2, its nuclear translocation and luciferase reporter gene expression under NFAT control. Overexpression of this fragment in Jurkat T cells suppresses the expression of luciferase controlled by the IL-2 promoter upon PMA/ionomycin stimulation .
RCAN1 and 2 contain a SP repeat motif binding to the catalytic centre of calcineurin. The SP repeat peptide (RCAN1-4 95-118 ), which can be phosphorylated by MAPK and GSK-3, simulates a substrate for calcineurin and thereby inhibits calcineurin activity against RII phosphopeptide in a competitive manner in cell-free assays. This inhibitory effect is independent of the phosphorylation status of the peptide. However, overexpressed RCAN1 fragments containing only the SP repeat domain do not suppress calcineurin-NFATc signalling in cells [184, 185]. A peptide containing the CIC motif and the C-terminal 30 amino acids of RCAN1 blocks dephosphorylation of the RII phosphopeptide by calcineurin, but neither the CIC containing peptide nor the C-terminus alone. It is suggested, that the C-terminal inhibitory motifs have to be in close proximity to calcineurin via binding of the CIC motif .
Calcineurin represents a crucial hub of T cell receptor-dependent signalling and controls the T cell activation mainly via NFATc dephosphorylation. Targeting this mechanism would enable pathogens to evade the host immune responses. Therefore, several viruses and bacteria have developed proteins inhibiting calcineurin-NFATc-dependent signalling. Characterizing these proteins might help to understand host defence mechanisms.
VacA is a protein from H. pylori, which inhibits the nuclear translocation of NFATc. In addition, VacA blocks ionomycin-induced increase of intracellular Ca2+ level, and the activation of the MKK3/6-p38 MAPK pathway. These data suggest multiple modes of VacA action, not all of them seem to be calcineurin-NFATc-dependent . However, VacA inhibits T cell activation, proliferation and IL-2 secretion in Jurkat cell lines and primary human CD4+ T cells [187, 188]. VacA is imported into the T cell via the receptors CD18 and LFA-1 . The expression of these cell surface proteins varies in different cell types, resulting in a different magnitude of inhibitory effects.
A238L, a protein of the african swine fever virus, seems to have different functions: first, to bind to calcineurin and inhibit its phosphatase activity and thus calcineurin-dependent pathways ; second, to suppress the acetylation and transcriptional activation of the transcription factors NFATc2, NF-κB, and c-Jun by inhibition of transactivation of the transcriptional co-activator CREB binding protein/p300 by PKCθ in stimulated human T cells ; and third, to inhibit the activation of JNK . Overexpression of A238L reduces calcineurin phosphatase activity against RII phosphopeptide in cell lysates and diminishes NFATc-dependent reporter gene expression in transfected porcine RS-2 kidney cells . It is speculated that A238L only inhibits the dephosphorylation of such NFATc residues which might be crucial for its transactivation function but has no effect on the dephosphorylation of the other residues required for nuclear translocation or DNA binding . Effects of A238L on NFATc-dependent gene transcription are abolished by co-overexpression of the constitutively active calcineurin construct ΔCaM-AI or NFATc2 in Jurkat T cells . Interestingly, A238L binds also to CypA, but this interaction seems to have no effect on A238L-calcineurin interaction .
The fragment A238L 157-238 contains a PxIxIT site (here: PKIIITG) and binds to calcineurin with high affinity. The 14 mer oligopeptide derived from this fragment A238L 200-213 binds to calcineurin even with a faster rate than the SPRIEIT peptide of porcine NFATc1 .
CsA and FK506 as well as some of their derivatives have become indispensible drugs to prevent transplant rejection and to treat dermatologic and autoimmune disorders. However, these drugs have a narrow therapeutic window. To reduce their adverse side effects different approaches were tested and some of them are still under investigation.
One strategy is to reduce the concentration of CsA and FK506, respectively, by combined application together with other immunosuppressive drugs having different modes of action, such as mycophenolate, rapamycin or monoclonal antibodies (e.g. Alemtuzumab). Another approach, especially in atopic dermatitis is to diminish systemic effects of the drugs by topical application of derivatives with enhanced lipophilic properties, such as pimecrolimus. A third approach is to apply CsA in low doses, thus taking advantage not only of its immunosuppressive, but also of its immunomodulatory properties .
Recently, some drugs originally introduced for applications other than inflammation turned out to act as inhibitors of calcineurin/NFATc activation. Among them are barbiturates, tropisetron and the acetaminophen/paracetamol catabolite AM404.
Application in basic research
Small molecular inhibitors and inhibitory peptides are valuable tools for a functional "knock-down" of cellular components to study the impact of different proteins, processes and pathways on specific cellular functions. Ideal inhibitors have to be monospecific, cell permeable and non-toxic. Most of the novel inhibitors, however, are not as well characterized as the "classical" inhibitors CsA and FK506.
Here we recommend the application of several inhibitors in basic research based on the intended investigations (Figure 2).
Inhibition of different Ser/Thr phosphatase activities
Norcantharidin inhibits PP1, PP2A and calcineurin with comparable efficacy. Okadaic acid or calyculin A can be used to discriminate between calcineurin and the other main Ser/Thr protein phosphatases when applied in the nanomolar concentration range. Under this condition they inhibit PP1 and PP2A, which account for more than 90% of the cellular Ser/Thr phosphatase activity, and additionally PP4, PP5 and PP6, but they fail to inhibit calcineurin.
Inhibition of calcineurin phosphatase activity without modulation of PPIases activities
Gossypol and kaempferol are useful to inhibit the phosphatase activity of calcineurin not only in enzymatic assays but also in primary cells due to their low cytotoxicity. They inhibit calcineurin without the need for a matchmaker protein. Both compounds, however, additionally inhibit several other cellular enzymes. Inhibitors of calcium signalling, e.g. BTP2 and trifluoperazine, suppress the activation of calcineurin but they also act on other Ca2+- or calmodulin-dependent processes, such as Ca2+-dependent PKCs or CaMKI/II. Peptides derived from the auto-inhibitory domain of calcineurin inhibit the phosphatase activity with high specificity, but their application is limited due to their reduced cell permeability.
Inhibition of NFATc dephosphorylation
NCI3 and dipyridamole are cell permeable compounds which inhibit NFATc dephosphorylation in cells without inhibition of the phosphatase activity of calcineurin in enzymatic assays. INCA-6 inhibits NFATc dephosphorylation and can be used in cell-free systems but is not recommended in primary cells due to its cytotoxicity. VIVIT peptide competes with NFATc for binding to calcineurin and is appropriate to inhibit NFATc dephosphorylation in cell-free assays.
Inhibition of NFATc-dependent gene transcription
BTP1, ST1959 and Roc-1 inhibit NFATc-dependent gene transcription presumably downstream of the calcineurin-NFATc interaction. These compounds are supposed to have no or low inhibitory effects on NF-κB or AP-1 activation.
Several other novel inhibitors of NFATc-dependent gene transcription have been isolated or synthesized. However, most of them have not been characterized so far and their molecular mode of action remains to be elucidated. Therefore, these compounds cannot be recommended as tools to dissect and define mechanisms of calcineurin action in the complex signalling network of cells.
In summary, CsA and FK506 are firmly established in the clinical routine. Several approaches are applied or under investigation to limit their side effects. In basic research, several more specific, although less well characterized, inhibitors of the calcineurin-NFATc axis can be utilized as alternatives. So far, their widespread application is hindered by a limited commercial availability.
List of abbreviations used
autoinhibitory domain of calcineurin
activator protein 1
green fluorescent protein
mitogen activated protein kinase
mixed lymphocyte reaction
nuclear factor of activated T cells, cytosolic
nuclear factor κB
peptidyl-prolyl cis-trans isomerase
T cell receptor
transforming growth factor β
We thank Peter Liman and Claudia Brandt for helpful comments about the application of immunosuppressants in clinical routine. The work was supported by the German Federal Ministry of Education and Research (BMBF) within the FORSYS Partner Initiative Berlin and by the Deutsche Forschungsgemeinschaft within the SFB52.
- Klee CB, Krinks MH: Purification of cyclic 3',5'-nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to Sepharose. Biochemistry. 1978, 17: 120-126. 10.1021/bi00594a017.PubMedView ArticleGoogle Scholar
- Crabtree GR, Olson EN: NFAT signaling: choreographing the social lives of cells. Cell. 2002, 109 (Suppl): S67-79. 10.1016/S0092-8674(02)00699-2.PubMedView ArticleGoogle Scholar
- Klee CB, Ren H, Wang X: Regulation of the calmodulin-stimulated protein phosphatase, calcineurin. J Biol Chem. 1998, 273: 13367-13370. 10.1074/jbc.273.22.13367.PubMedView ArticleGoogle Scholar
- Liu JO: Endogenous protein inhibitors of calcineurin. Biochem Biophys Res Commun. 2003, 311: 1103-1109. 10.1016/j.bbrc.2003.10.020.PubMedView ArticleGoogle Scholar
- Liu JO: Calmodulin-dependent phosphatase, kinases, and transcriptional corepressors involved in T-cell activation. Immunol Rev. 2009, 228: 184-198. 10.1111/j.1600-065X.2008.00756.x.PubMed CentralPubMedView ArticleGoogle Scholar
- Morioka M, Hamada J, Ushio Y, Miyamoto E: Potential role of calcineurin for brain ischemia and traumatic injury. Prog Neurobiol. 1999, 58: 1-30. 10.1016/S0301-0082(98)00073-2.PubMedView ArticleGoogle Scholar
- Rao A, Luo C, Hogan PG: Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 1997, 15: 707-747. 10.1146/annurev.immunol.15.1.707.PubMedView ArticleGoogle Scholar
- Serfling E, Berberich-Siebelt F, Chuvpilo S, Jankevics E, Klein-Hessling S, Twardzik T, Avots A: The role of NF-AT transcription factors in T cell activation and differentiation. Biochim Biophys Acta. 2000, 1498: 1-18. 10.1016/S0167-4889(00)00082-3.PubMedView ArticleGoogle Scholar
- Hogan PG, Chen L, Nardone J, Rao A: Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003, 17: 2205-2232. 10.1101/gad.1102703.PubMedView ArticleGoogle Scholar
- Macian F: NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005, 5: 472-484. 10.1038/nri1632.PubMedView ArticleGoogle Scholar
- Yang J, Rothermel B, Vega RB, Frey N, McKinsey TA, Olson EN, Bassel-Duby R, Williams RS: Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res. 2000, 87: E61-68.PubMedView ArticleGoogle Scholar
- Batiuk TD, Halloran PF: The downstream consequences of calcineurin inhibition. Transplant Proc. 1997, 29: 1239-1240. 10.1016/S0041-1345(96)00481-2.PubMedView ArticleGoogle Scholar
- Graef IA, Chen F, Chen L, Kuo A, Crabtree GR: Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature. Cell. 2001, 105: 863-875. 10.1016/S0092-8674(01)00396-8.PubMedView ArticleGoogle Scholar
- Bueno OF, Brandt EB, Rothenberg ME, Molkentin JD: Defective T cell development and function in calcineurin A beta-deficient mice. Proc Natl Acad Sci USA. 2002, 99: 9398-9403. 10.1073/pnas.152665399.PubMed CentralPubMedView ArticleGoogle Scholar
- Okamura H, Aramburu J, Garcia-Rodriguez C, Viola JP, Raghavan A, Tahiliani M, Zhang X, Qin J, Hogan PG, Rao A: Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol Cell. 2000, 6: 539-550. 10.1016/S1097-2765(00)00053-8.PubMedView ArticleGoogle Scholar
- Luo C, Shaw KT, Raghavan A, Aramburu J, Garcia-Cozar F, Perrino BA, Hogan PG, Rao A: Interaction of calcineurin with a domain of the transcription factor NFAT1 that controls nuclear import. Proc Natl Acad Sci USA. 1996, 93: 8907-8912. 10.1073/pnas.93.17.8907.PubMed CentralPubMedView ArticleGoogle Scholar
- Zhu J, Shibasaki F, Price R, Guillemot JC, Yano T, Dotsch V, Wagner G, Ferrara P, McKeon F: Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell. 1998, 93: 851-861. 10.1016/S0092-8674(00)81445-2.PubMedView ArticleGoogle Scholar
- Beals CR, Sheridan CM, Turck CW, Gardner P, Crabtree GR: Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science. 1997, 275: 1930-1934. 10.1126/science.275.5308.1930.PubMedView ArticleGoogle Scholar
- Okamura H, Garcia-Rodriguez C, Martinson H, Qin J, Virshup DM, Rao A: A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol Cell Biol. 2004, 24: 4184-4195. 10.1128/MCB.24.10.4184-4195.2004.PubMed CentralPubMedView ArticleGoogle Scholar
- Liu J, Masuda ES, Tsuruta L, Arai N, Arai K: Two independent calcineurin-binding regions in the N-terminal domain of murine NF-ATx1 recruit calcineurin to murine NF-ATx1. J Immunol. 1999, 162: 4755-4761.PubMedGoogle Scholar
- Aramburu J, Garcia-Cozar F, Raghavan A, Okamura H, Rao A, Hogan PG: Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol Cell. 1998, 1: 627-637. 10.1016/S1097-2765(00)80063-5.PubMedView ArticleGoogle Scholar
- Garcia-Cozar FJ, Okamura H, Aramburu JF, Shaw KT, Pelletier L, Showalter R, Villafranca E, Rao A: Two-site interaction of nuclear factor of activated T cells with activated calcineurin. J Biol Chem. 1998, 273: 23877-23883. 10.1074/jbc.273.37.23877.PubMedView ArticleGoogle Scholar
- Martinez-Martinez S, Rodriguez A, Lopez-Maderuelo MD, Ortega-Perez I, Vazquez J, Redondo JM: Blockade of NFAT activation by the second calcineurin binding site. J Biol Chem. 2006, 281: 6227-6235. 10.1074/jbc.M513885200.PubMedView ArticleGoogle Scholar
- Rodriguez A, Roy J, Martinez-Martinez S, Lopez-Maderuelo MD, Nino-Moreno P, Orti L, Pantoja-Uceda D, Pineda-Lucena A, Cyert MS, Redondo JM: A conserved docking surface on calcineurin mediates interaction with substrates and immunosuppressants. Mol Cell. 2009, 33: 616-626. 10.1016/j.molcel.2009.01.030.PubMed CentralPubMedView ArticleGoogle Scholar
- Li H, Zhang L, Rao A, Harrison SC, Hogan PG: Structure of calcineurin in complex with PVIVIT peptide: portrait of a low-affinity signalling interaction. J Mol Biol. 2007, 369: 1296-1306. 10.1016/j.jmb.2007.04.032.PubMedView ArticleGoogle Scholar
- Roy J, Li H, Hogan PG, Cyert MS: A conserved docking site modulates substrate affinity for calcineurin, signaling output, and in vivo function. Mol Cell. 2007, 25: 889-901. 10.1016/j.molcel.2007.02.014.PubMed CentralPubMedView ArticleGoogle Scholar
- Frantz B, Nordby EC, Bren G, Steffan N, Paya CV, Kincaid RL, Tocci MJ, O'Keefe SJ, O'Neill EA: Calcineurin acts in synergy with PMA to inactivate I kappa B/MAD3, an inhibitor of NF-kappa B. Embo J. 1994, 13: 861-870.PubMed CentralPubMedGoogle Scholar
- Sugimoto T, Stewart S, Guan KL: The calcium/calmodulin-dependent protein phosphatase calcineurin is the major Elk-1 phosphatase. J Biol Chem. 1997, 272: 29415-29418. 10.1074/jbc.272.47.29415.PubMedView ArticleGoogle Scholar
- Dolmetsch RE, Xu K, Lewis RS: Calcium oscillations increase the efficiency and specificity of gene expression. Nature. 1998, 392: 933-936. 10.1038/31960.PubMedView ArticleGoogle Scholar
- Alzuherri H, Chang KC: Calcineurin activates NF-kappaB in skeletal muscle C2C12 cells. Cell Signal. 2003, 15: 471-478. 10.1016/S0898-6568(02)00120-1.PubMedView ArticleGoogle Scholar
- Valdes JA, Hidalgo J, Galaz JL, Puentes N, Silva M, Jaimovich E, Carrasco MA: NF-kappaB activation by depolarization of skeletal muscle cells depends on ryanodine and IP3 receptor-mediated calcium signals. Am J Physiol Cell Physiol. 2007, 292: C1960-1970. 10.1152/ajpcell.00320.2006.PubMedView ArticleGoogle Scholar
- Guo L, Urban JF, Zhu J, Paul WE: Elevating calcium in Th2 cells activates multiple pathways to induce IL-4 transcription and mRNA stabilization. J Immunol. 2008, 181: 3984-3993.PubMed CentralPubMedView ArticleGoogle Scholar
- Liu Q, Busby JC, Molkentin JD: Interaction between TAK1-TAB1-TAB2 and RCAN1-calcineurin defines a signalling nodal control point. Nat Cell Biol. 2009, 11: 154-161. 10.1038/ncb1823.PubMed CentralPubMedView ArticleGoogle Scholar
- Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K: The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway. Nature. 1999, 398: 252-256. 10.1038/18465.PubMedView ArticleGoogle Scholar
- Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, Swanson SJ, Mannon RB, Roederer M, Kirk AD: Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 2005, 5: 465-474.PubMedView ArticleGoogle Scholar
- Jones DL, Sacks SH, Wong W: Controlling the generation and function of human CD8+ memory T cells in vitro with immunosuppressants. Transplantation. 2006, 82: 1352-1361. 10.1097/01.tp.0000241077.83511.be.PubMedView ArticleGoogle Scholar
- Taylor AL, Watson CJ, Bradley JA: Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol. 2005, 56: 23-46. 10.1016/j.critrevonc.2005.03.012.PubMedView ArticleGoogle Scholar
- El-Batawy MM, Bosseila MA, Mashaly HM, Hafez VS: Topical calcineurin inhibitors in atopic dermatitis: a systematic review and meta-analysis. J Dermatol Sci. 2009, 54: 76-87. 10.1016/j.jdermsci.2009.02.002.PubMedView ArticleGoogle Scholar
- Brandt C, Pavlovic V, Radbruch A, Worm M, Baumgrass R: Low-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis. Allergy. 2009, 64: 1588-1596. 10.1111/j.1398-9995.2009.02054.x.PubMedView ArticleGoogle Scholar
- Rusnak F, Mertz P: Calcineurin: form and function. Physiol Rev. 2000, 80: 1483-1521.PubMedGoogle Scholar
- Sugiura R, Sio SO, Shuntoh H, Kuno T: Molecular genetic analysis of the calcineurin signaling pathways. Cell Mol Life Sci. 2001, 58: 278-288. 10.1007/PL00000855.PubMedView ArticleGoogle Scholar
- Borel JF, Feurer C, Gubler HU, Stahelin H: Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976, 6: 468-475. 10.1007/BF01973261.PubMedView ArticleGoogle Scholar
- Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Henderson RG, Aziz S, Lewis P: Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979, 2: 1033-1036. 10.1016/S0140-6736(79)92440-1.PubMedView ArticleGoogle Scholar
- Starzl TE, Weil R, Iwatsuki S, Klintmalm G, Schroter GP, Koep LJ, Iwaki Y, Terasaki PI, Porter KA: The use of cyclosporin A and prednisone in cadaver kidney transplantation. Surg Gynecol Obstet. 1980, 151: 17-26.PubMed CentralPubMedGoogle Scholar
- Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987, 40: 1249-1255.View ArticleGoogle Scholar
- Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A: FK 506 for liver, kidney, and pancreas transplantation. Lancet. 1989, 2: 1000-1004. 10.1016/S0140-6736(89)91014-3.PubMed CentralPubMedView ArticleGoogle Scholar
- Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991, 66: 807-815. 10.1016/0092-8674(91)90124-H.PubMedView ArticleGoogle Scholar
- Schreiber SL, Crabtree GR: The mechanism of action of cyclosporin A and FK506. Immunol Today. 1992, 13: 136-142. 10.1016/0167-5699(92)90111-J.PubMedView ArticleGoogle Scholar
- Barik S: Immunophilins: for the love of proteins. Cell Mol Life Sci. 2006, 63: 2889-2900. 10.1007/s00018-006-6215-3.PubMedView ArticleGoogle Scholar
- Kang CB, Hong Y, Dhe-Paganon S, Yoon HS: FKBP family proteins: immunophilins with versatile biological functions. Neurosignals. 2008, 16: 318-325. 10.1159/000123041.PubMedView ArticleGoogle Scholar
- Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA: X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell. 1995, 82: 507-522. 10.1016/0092-8674(95)90439-5.PubMedView ArticleGoogle Scholar
- Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al.: Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature. 1995, 378: 641-644. 10.1038/378641a0.PubMedView ArticleGoogle Scholar
- Huai Q, Kim HY, Liu Y, Zhao Y, Mondragon A, Liu JO, Ke H: Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes. Proc Natl Acad Sci USA. 2002, 99: 12037-12042. 10.1073/pnas.192206699.PubMed CentralPubMedView ArticleGoogle Scholar
- Jin L, Harrison SC: Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin. Proc Natl Acad Sci USA. 2002, 99: 13522-13526. 10.1073/pnas.212504399.PubMed CentralPubMedView ArticleGoogle Scholar
- Swanson SK, Born T, Zydowsky LD, Cho H, Chang HY, Walsh CT, Rusnak F: Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Proc Natl Acad Sci USA. 1992, 89: 3741-3745. 10.1073/pnas.89.9.3741.PubMed CentralPubMedView ArticleGoogle Scholar
- Yin M, Ochs RS: Mechanism for the paradoxical inhibition and stimulation of calcineurin by the immunosuppresive drug tacrolimus (FK506). Arch Biochem Biophys. 2003, 419: 207-213. 10.1016/j.abb.2003.09.003.PubMedView ArticleGoogle Scholar
- Handschumacher RE, Harding MW, Rice J, Drugge RJ, Speicher DW: Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science. 1984, 226: 544-547. 10.1126/science.6238408.PubMedView ArticleGoogle Scholar
- Siekierka JJ, Hung SH, Poe M, Lin CS, Sigal NH: A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature. 1989, 341: 755-757. 10.1038/341755a0.PubMedView ArticleGoogle Scholar
- Harding MW, Galat A, Uehling DE, Schreiber SL: A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature. 1989, 341: 758-760. 10.1038/341758a0.PubMedView ArticleGoogle Scholar
- Kalli K, Huntoon C, Bell M, McKean DJ: Mechanism responsible for T-cell antigen receptor- and CD28- or interleukin 1 (IL-1) receptor-initiated regulation of IL-2 gene expression by NF-kappaB. Mol Cell Biol. 1998, 18: 3140-3148.PubMed CentralPubMedView ArticleGoogle Scholar
- Aoki Y, Kao PN: Erythromycin inhibits transcriptional activation of NF-kappaB, but not NFAT, through calcineurin-independent signaling in T cells. Antimicrob Agents Chemother. 1999, 43: 2678-2684.PubMed CentralPubMedGoogle Scholar
- Steffan NM, Bren GD, Frantz B, Tocci MJ, O'Neill EA, Paya CV: Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways. J Immunol. 1995, 155: 4685-4691.PubMedGoogle Scholar
- Oetjen E, Thoms KM, Laufer Y, Pape D, Blume R, Li P, Knepel W: The immunosuppressive drugs cyclosporin A and tacrolimus inhibit membrane depolarization-induced CREB transcriptional activity at the coactivator level. Br J Pharmacol. 2005, 144: 982-993. 10.1038/sj.bjp.0706127.PubMed CentralPubMedView ArticleGoogle Scholar
- Marienfeld R, Neumann M, Chuvpilo S, Escher C, Kneitz B, Avots A, Schimpl A, Serfling E: Cyclosporin A interferes with the inducible degradation of NF-kappa B inhibitors, but not with the processing of p105/NF-kappa B1 in T cells. Eur J Immunol. 1997, 27: 1601-1609. 10.1002/eji.1830270703.PubMedView ArticleGoogle Scholar
- Meyer S, Kohler NG, Joly A: Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-kappaB activation. FEBS Lett. 1997, 413: 354-358. 10.1016/S0014-5793(97)00930-7.PubMedView ArticleGoogle Scholar
- Nickel P, Presber F, Bold G, Biti D, Schonemann C, Tullius SG, Volk HD, Reinke P: Enzyme-linked immunosorbent spot assay for donor-reactive interferon-gamma-producing cells identifies T-cell presensitization and correlates with graft function at 6 and 12 months in renal-transplant recipients. Transplantation. 2004, 78: 1640-1646. 10.1097/01.TP.0000144057.31799.6A.PubMedView ArticleGoogle Scholar
- Naesens M, Kuypers DR, Sarwal M: Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009, 4: 481-508.PubMedGoogle Scholar
- Kiani A, Rao A, Aramburu J: Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity. 2000, 12: 359-372. 10.1016/S1074-7613(00)80188-0.PubMedView ArticleGoogle Scholar
- Zhang Y, Baumgrass R, Schutkowski M, Fischer G: Branches on the alpha-C atom of cyclosporin A residue 3 result in direct calcineurin inhibition and rapid cyclophilin 18 binding. Chembiochem. 2004, 5: 1006-1009. 10.1002/cbic.200400020.PubMedView ArticleGoogle Scholar
- Durette PL, Boger J, Dumont F, Firestone R, Frankshun RA, Koprak SL, Lin CS, Melino MR, Pessolano AA, Pisano J, et al.: A study of the correlation between cyclophilin binding and in vitro immunosuppressive activity of cyclosporine A and analogues. Transplant Proc. 1988, 20: 51-57.PubMedGoogle Scholar
- Sigal NH, Dumont F, Durette P, Siekierka JJ, Peterson L, Rich DH, Dunlap BE, Staruch MJ, Melino MR, Koprak SL, et al.: Is cyclophilin involved in the immunosuppressive and nephrotoxic mechanism of action of cyclosporin A?. J Exp Med. 1991, 173: 619-628. 10.1084/jem.173.3.619.PubMedView ArticleGoogle Scholar
- Nelson PA, Akselband Y, Kawamura A, Su M, Tung RD, Rich DH, Kishore V, Rosborough SL, DeCenzo MT, Livingston DJ, et al.: Immunosuppressive activity of [MeBm2t]1-, D-diaminobutyryl-8-, and D-diaminopropyl-8-cyclosporin analogues correlates with inhibition of calcineurin phosphatase activity. J Immunol. 1993, 150: 2139-2147.PubMedGoogle Scholar
- Baumgrass R, Zhang Y, Erdmann F, Thiel A, Weiwad M, Radbruch A, Fischer G: Substitution in position 3 of cyclosporin A abolishes the cyclophilin-mediated gain-of-function mechanism but not immunosuppression. J Biol Chem. 2004, 279: 2470-2479. 10.1074/jbc.M304754200.PubMedView ArticleGoogle Scholar
- Aebi JD, Deyo DT, Sun CQ, Guillaume D, Dunlap B, Rich DH: Synthesis, conformation, and immunosuppressive activities of three analogues of cyclosporin A modified in the 1-position. J Med Chem. 1990, 33: 999-1009. 10.1021/jm00165a018.PubMedView ArticleGoogle Scholar
- Aspeslet L, Freitag D, Trepanier D, Abel M, Naicker S, Kneteman N, Foster R, Yatscoff R: ISA(TX)247: a novel calcineurin inhibitor. Transplant Proc. 2001, 33: 1048-1051. 10.1016/S0041-1345(00)02325-3.PubMedView ArticleGoogle Scholar
- Birsan T, Dambrin C, Freitag DG, Yatscoff RW, Morris RE: The novel calcineurin inhibitor ISA247: a more potent immunosuppressant than cyclosporine in vitro. Transpl Int. 2005, 17: 767-771. 10.1111/j.1432-2277.2004.tb00509.x.PubMedView ArticleGoogle Scholar
- Maksymowych WP, Jhangri GS, Aspeslet L, Abel MD, Trepanier DJ, Naicker S, Freitag DG, Cooper BL, Foster RT, Yatscoff RW: Amelioration of accelerated collagen induced arthritis by a novel calcineurin inhibitor, ISA(TX)247. J Rheumatol. 2002, 29: 1646-1652.PubMedGoogle Scholar
- Naidoo P, Rambiritch V: Voclosporin (ISA247) for plaque psoriasis. Lancet. 2008, 372: 888-889. 10.1016/S0140-6736(08)61391-4. author reply 889.PubMedView ArticleGoogle Scholar
- Dumont FJ, Staruch MJ, Koprak SL, Siekierka JJ, Lin CS, Harrison R, Sewell T, Kindt VM, Beattie TR, Wyvratt M, et al.: The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin. J Exp Med. 1992, 176: 751-760. 10.1084/jem.176.3.751.PubMedView ArticleGoogle Scholar
- Klettner A, Baumgrass R, Zhang Y, Fischer G, Burger E, Herdegen T, Mielke K: The neuroprotective actions of FK506 binding protein ligands: neuronal survival is triggered by de novo RNA synthesis, but is independent of inhibition of JNK and calcineurin. Brain Res Mol Brain Res. 2001, 97: 21-31. 10.1016/S0169-328X(01)00286-8.PubMedView ArticleGoogle Scholar
- Liu J, Albers MW, Wandless TJ, Luan S, Alberg DG, Belshaw PJ, Cohen P, MacKintosh C, Klee CB, Schreiber SL: Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry. 1992, 31: 3896-3901. 10.1021/bi00131a002.PubMedView ArticleGoogle Scholar
- Grassberger M, Baumruker T, Enz A, Hiestand P, Hultsch T, Kalthoff F, Schuler W, Schulz M, Werner FJ, Winiski A, et al.: A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol. 1999, 141: 264-273. 10.1046/j.1365-2133.1999.02974.x.PubMedView ArticleGoogle Scholar
- Peterson LB, Cryan JG, Rosa R, Martin MM, Wilusz MB, Sinclair PJ, Wong F, Parsons JN, O'Keefe SJ, Parsons WH, et al.: A tacrolimus-related immunosuppressant with biochemical properties distinct from those of tacrolimus. Transplantation. 1998, 65: 10-18. 10.1097/00007890-199801150-00004.PubMedView ArticleGoogle Scholar
- Dumont FJ, Koprak S, Staruch MJ, Talento A, Koo G, DaSilva C, Sinclair PJ, Wong F, Woods J, Barker J, et al.: A tacrolimus-related immunosuppressant with reduced toxicity. Transplantation. 1998, 65: 18-26. 10.1097/00007890-199801150-00005.PubMedView ArticleGoogle Scholar
- Schreiber SL: Chemistry and biology of the immunophilins and their immunosuppressive ligands. Science. 1991, 251: 283-287. 10.1126/science.1702904.PubMedView ArticleGoogle Scholar
- Thomson AW, Turnquist HR, Raimondi G: Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol. 2009, 9: 324-337. 10.1038/nri2546.PubMed CentralPubMedView ArticleGoogle Scholar
- Campistol JM: Minimizing the risk of posttransplant malignancy. Transplantation. 2009, 87: S19-22.PubMedView ArticleGoogle Scholar
- Born TL, Myers JK, Widlanski TS, Rusnak F: 4-(Fluoromethyl)phenyl phosphate acts as a mechanism-based inhibitor of calcineurin. J Biol Chem. 1995, 270: 25651-25655. 10.1074/jbc.270.43.25651.PubMedView ArticleGoogle Scholar
- Martin BL: Inhibition of calcineurin by the tyrphostin class of tyrosine kinase inhibitors. Biochem Pharmacol. 1998, 56: 483-488. 10.1016/S0006-2952(98)00181-6.PubMedView ArticleGoogle Scholar
- Stewart SG, Hill TA, Gilbert J, Ackland SP, Sakoff JA, McCluskey A: Synthesis and biological evaluation of norcantharidin analogues: towards PP1 selectivity. Bioorg Med Chem. 2007, 15: 7301-7310. 10.1016/j.bmc.2007.08.028.PubMedView ArticleGoogle Scholar
- Weiser DC, Shenolikar S: Use of protein phosphatase inhibitors. Curr Protoc Protein Sci. 2003, Chapter 13 (Unit 13): 10-PubMedGoogle Scholar
- Enz A, Pombo-Villar E: Class II pyrethroids: noninhibitors calcineurin. Biochem Pharmacol. 1997, 54: 321-323. 10.1016/S0006-2952(97)00175-5.PubMedView ArticleGoogle Scholar
- Fakata KL, Swanson SA, Vorce RL, Stemmer PM: Pyrethroid insecticides as phosphatase inhibitors. Biochem Pharmacol. 1998, 55: 2017-2022. 10.1016/S0006-2952(98)00076-8.PubMedView ArticleGoogle Scholar
- Wang H, Zhou CL, Lei H, Zhang SD, Zheng J, Wei Q: Kaempferol: a new immunosuppressant of calcineurin. IUBMB Life. 2008, 60: 549-554. 10.1002/iub.94.PubMedView ArticleGoogle Scholar
- Lei H, Qi Y, Jia ZG, Lin WL, Wei Q: Studies on the interactions of kaempferol to calcineurin by spectroscopic methods and docking. Biochim Biophys Acta. 2009, 1794: 1269-1275.PubMedView ArticleGoogle Scholar
- Lee S, Kim YJ, Kwon S, Lee Y, Choi SY, Park J, Kwon HJ: Inhibitory effects of flavonoids on TNF-alpha-induced IL-8 gene expression in HEK 293 cells. BMB Rep. 2009, 42: 265-270.PubMedView ArticleGoogle Scholar
- Humar M, Pischke SE, Loop T, Hoetzel A, Schmidt R, Klaas C, Pahl HL, Geiger KK, Pannen BH: Barbiturates directly inhibit the calmodulin/calcineurin complex: a novel mechanism of inhibition of nuclear factor of activated T cells. Mol Pharmacol. 2004, 65: 350-361. 10.1124/mol.65.2.350.PubMedView ArticleGoogle Scholar
- Humar M, Dohrmann H, Stein P, Andriopoulos N, Goebel U, Heimrich B, Roesslein M, Schmidt R, Schwer CI, Hoetzel A, et al.: Repression of T-cell function by thionamides is mediated by inhibition of the activator protein-1/nuclear factor of activated T-cells pathway and is associated with a common structure. Mol Pharmacol. 2007, 72: 1647-1656. 10.1124/mol.107.038141.PubMedView ArticleGoogle Scholar
- Loop T, Liu Z, Humar M, Hoetzel A, Benzing A, Pahl HL, Geiger KK, BH JP: Thiopental inhibits the activation of nuclear factor kappaB. Anesthesiology. 2002, 96: 1202-1213. 10.1097/00000542-200205000-00025.PubMedView ArticleGoogle Scholar
- Correa-Sales C, Tosta CE, Rizzo LV: The effects of anesthesia with thiopental on T lymphocyte responses to antigen and mitogens in vivo and in vitro. Int J Immunopharmacol. 1997, 19: 117-128. 10.1016/S0192-0561(97)00003-9.PubMedView ArticleGoogle Scholar
- Baba Y, Hirukawa N, Tanohira N, Sodeoka M: Structure-based design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (calcineurin). J Am Chem Soc. 2003, 125: 9740-9749. 10.1021/ja034694y.PubMedView ArticleGoogle Scholar
- Baba Y, Hirukawa N, Sodeoka M: Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin): implications for the binding mode. Bioorg Med Chem. 2005, 13: 5164-5170. 10.1016/j.bmc.2005.05.013.PubMedView ArticleGoogle Scholar
- Carruthers NJ, Dowd MK, Stemmer PM: Gossypol inhibits calcineurin phosphatase activity at multiple sites. Eur J Pharmacol. 2007, 555: 106-114. 10.1016/j.ejphar.2006.10.046.PubMedView ArticleGoogle Scholar
- Xu WB, Xu LH, Lu HS, Ou-Yang DY, Shi HJ, Di JF, He XH: The immunosuppressive effect of gossypol in mice is mediated by inhibition of lymphocyte proliferation and by induction of cell apoptosis. Acta Pharmacol Sin. 2009, 30: 597-604. 10.1038/aps.2009.35.PubMed CentralPubMedView ArticleGoogle Scholar
- Weissenmayer B, Boeckeler K, Lahrz A, Mutzel R: The calcineurin inhibitor gossypol impairs growth, cell signalling and development in Dictyostelium discoideum. FEMS Microbiol Lett. 2005, 242: 19-25. 10.1016/j.femsle.2004.10.035.PubMedView ArticleGoogle Scholar
- Gomez MS, Piper RC, Hunsaker LA, Royer RE, Deck LM, Makler MT, Jagt Vander DL: Substrate and cofactor specificity and selective inhibition of lactate dehydrogenase from the malarial parasite P. falciparum. Mol Biochem Parasitol. 1997, 90: 235-246. 10.1016/S0166-6851(97)00140-0.PubMedView ArticleGoogle Scholar
- Yu BZ, Rogers J, Ranadive G, Baker S, Wilton DC, Apitz-Castro R, Jain MK: Gossypol modification of Ala-1 of secreted phospholipase A2: a probe for the kinetic effects of sulfate glycoconjugates. Biochemistry. 1997, 36: 12400-12411. 10.1021/bi962972i.PubMedView ArticleGoogle Scholar
- Adlakha RC, Ashorn CL, Chan D, Zwelling LA: Modulation of 4'-(9-acridinylamino)methanesulfon-m-anisidide-induced, topoisomerase II-mediated DNA cleavage by gossypol. Cancer Res. 1989, 49: 2052-2058.PubMedGoogle Scholar
- Gualberto A, Marquez G, Carballo M, Youngblood GL, Hunt SW, Baldwin AS, Sobrino F: p53 transactivation of the HIV-1 long terminal repeat is blocked by PD 14 a calcineurin-inhibitor with anti-HIV properties. J Biol Chem. 1998, 273 (12): 7088-7093. 10.1074/jbc.273.12.7088.PubMedView ArticleGoogle Scholar
- Brill GM, Premachandran U, Karwowski JP, Henry R, Cwik DK, Traphagen LM, Humphrey PE, Jackson M, Clement JJ, Burres NS, et al.: Dibefurin, a novel fungal metabolite inhibiting calcineurin phosphatase activity. J Antibiot (Tokyo). 1996, 49: 124-128.View ArticleGoogle Scholar
- Mulero MC, Aubareda A, Orzaez M, Messeguer J, Serrano-Candelas E, Martinez-Hoyer S, Messeguer A, Perez-Paya E, Perez-Riba M: Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity. J Biol Chem. 2009, 284: 9394-9401. 10.1074/jbc.M805889200.PubMed CentralPubMedView ArticleGoogle Scholar
- Borisy AA, Elliott PJ, Hurst NW, Lee MS, Lehar J, Price ER, Serbedzija G, Zimmermann GR, Foley MA, Stockwell BR, Keith CT: Systematic discovery of multicomponent therapeutics. Proc Natl Acad Sci USA. 2003, 100: 7977-7982. 10.1073/pnas.1337088100.PubMed CentralPubMedView ArticleGoogle Scholar
- Sieber M, Karanik M, Brandt C, Blex C, Podtschaske M, Erdmann F, Rost R, Serfling E, Liebscher J, Patzel M, et al.: Inhibition of calcineurin-NFAT signaling by the pyrazolopyrimidine compound NCI3. Eur J Immunol. 2007, 37: 2617-2626. 10.1002/eji.200737087.PubMedView ArticleGoogle Scholar
- Roehrl MH, Kang S, Aramburu J, Wagner G, Rao A, Hogan PG: Selective inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with small organic molecules. Proc Natl Acad Sci USA. 2004, 101: 7554-7559. 10.1073/pnas.0401835101.PubMed CentralPubMedView ArticleGoogle Scholar
- Kang S, Li H, Rao A, Hogan PG: Inhibition of the calcineurin-NFAT interaction by small organic molecules reflects binding at an allosteric site. J Biol Chem. 2005, 280: 37698-37706. 10.1074/jbc.M502247200.PubMedView ArticleGoogle Scholar
- Djuric SW, BaMaung NY, Basha A, Liu H, Luly JR, Madar DJ, Sciotti RJ, Tu NP, Wagenaar FL, Wiedeman PE, et al.: 3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator. J Med Chem. 2000, 43: 2975-2981. 10.1021/jm990615a.PubMedView ArticleGoogle Scholar
- Chen Y, Smith ML, Chiou GX, Ballaron S, Sheets MP, Gubbins E, Warrior U, Wilkins J, Surowy C, Nakane M, et al.: TH1 and TH2 cytokine inhibition by 3,5-bis(trifluoromethyl)pyrazoles, a novel class of immunomodulators. Cell Immunol. 2002, 220: 134-142. 10.1016/S0008-8749(03)00005-4.PubMedView ArticleGoogle Scholar
- Trevillyan JM, Chiou XG, Chen YW, Ballaron SJ, Sheets MP, Smith ML, Wiedeman PE, Warrior U, Wilkins J, Gubbins EJ, et al.: Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds. J Biol Chem. 2001, 276: 48118-48126.PubMedGoogle Scholar
- Ishikawa J, Ohga K, Yoshino T, Takezawa R, Ichikawa A, Kubota H, Yamada T: A pyrazole derivative, YM-58483 potently inhibits store-operated sustained Ca2+ influx and IL-2 production in T lymphocytes. J Immunol. 2003, 170 (9): 4441-4449.PubMedView ArticleGoogle Scholar
- Zitt C, Strauss B, Schwarz EC, Spaeth N, Rast G, Hatzelmann A, Hoth M: Potent inhibition of Ca2+ release-activated Ca2+ channels and T-lymphocyte activation by the pyrazole derivative BTP2. J Biol Chem. 2004, 279: 12427-12437. 10.1074/jbc.M309297200.PubMedView ArticleGoogle Scholar
- Takezawa R, Cheng H, Beck A, Ishikawa J, Launay P, Kubota H, Kinet JP, Fleig A, Yamada T, Penner R: A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating transient receptor potential melastatin 4 channel activity. Mol Pharmacol. 2006, 69: 1413-1420. 10.1124/mol.105.021154.PubMedView ArticleGoogle Scholar
- Yoshino T, Ishikawa J, Ohga K, Morokata T, Takezawa R, Morio H, Okada Y, Honda K, Yamada T: YM-58483 a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models. Eur J Pharmacol. 2007, 560 (2-3): 225-233. 10.1016/j.ejphar.2007.01.012.PubMedView ArticleGoogle Scholar
- Ohga K, Takezawa R, Arakida Y, Shimizu Y, Ishikawa J: Characterization of YM-58483/BTP2, a novel store-operated Ca2+ entry blocker, on T cell-mediated immune responses in vivo. Int Immunopharmacol. 2008, 8: 1787-1792. 10.1016/j.intimp.2008.08.016.PubMedView ArticleGoogle Scholar
- Steinckwich N, Frippiat JP, Stasia MJ, Erard M, Boxio R, Tankosic C, Doignon I, Nusse O: Potent inhibition of store-operated Ca2+ influx and superoxide production in HL60 cells and polymorphonuclear neutrophils by the pyrazole derivative BTP2. J Leukoc Biol. 2007, 81: 1054-1064. 10.1189/jlb.0406248.PubMedView ArticleGoogle Scholar
- Birsan T, Dambrin C, Marsh KC, Jacobsen W, Djuric SW, Mollison KW, Christians U, Carter GW, Morris RE: Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin-independent inhibitor of NFAT. Transpl Int. 2004, 17: 145-150.PubMedView ArticleGoogle Scholar
- Nilsson LM, Sun ZW, Nilsson J, Nordstrom I, Chen YW, Molkentin JD, Wide-Swensson D, Hellstrand P, Lydrup ML, Gomez MF: Novel blocker of NFAT activation inhibits IL-6 production in human myometrial arteries and reduces vascular smooth muscle cell proliferation. Am J Physiol Cell Physiol. 2007, 292: C1167-1178. 10.1152/ajpcell.00590.2005.PubMedView ArticleGoogle Scholar
- Jabr RI, Wilson AJ, Riddervold MH, Jenkins AH, Perrino BA, Clapp LH: Nuclear translocation of calcineurin Abeta but not calcineurin Aalpha by platelet-derived growth factor in rat aortic smooth muscle. Am J Physiol Cell Physiol. 2007, 292: C2213-2225. 10.1152/ajpcell.00139.2005.PubMedView ArticleGoogle Scholar
- Lindstedt R, Ruggiero V, D'Alessio DA, Manganello S, Petronzelli F, Stasi MA, Vendetti S, Assandri A, Carminati P, De Santis R: The immunosuppressor st1959 a 3,5-diaryl-s-triazole derivative, inhibits T cell activation by reducing NFAT nuclear residency. Int J Immunopathol Pharmacol. 2009, 22 (1): 29-42.PubMedGoogle Scholar
- Mistrello G, Galliani G, Assandri A, Filippeschi S, Bassi L: Immunological profile of DL111-IT, a new immunosuppressant agent. Immunopharmacology. 1985, 10: 163-169. 10.1016/0162-3109(85)90022-0.PubMedView ArticleGoogle Scholar
- Campo S, Arseni B, Rossi S, D'Alessio V, Lu R, Ngoje J, Ahl PL, Bonitz S, Mannino R, Di Mitri D, et al.: Efficacy of a nanocochleate-encapsulated 3,5-diaryl-s-triazole derivative in a murine model of graft-versus-host disease. Transplantation. 2008, 86: 171-175. 10.1097/TP.0b013e31817ba761.PubMedView ArticleGoogle Scholar
- Hogestatt ED, Jonsson BA, Ermund A, Andersson DA, Bjork H, Alexander JP, Cravatt BF, Basbaum AI, Zygmunt PM: Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Biol Chem. 2005, 280: 31405-31412. 10.1074/jbc.M501489200.PubMedView ArticleGoogle Scholar
- Caballero FJ, Navarrete CM, Hess S, Fiebich BL, Appendino G, Macho A, Munoz E, Sancho R: The acetaminophen-derived bioactive N-acylphenolamine AM404 inhibits NFAT by targeting nuclear regulatory events. Biochem Pharmacol. 2007, 73: 1013-1023. 10.1016/j.bcp.2006.12.001.PubMedView ArticleGoogle Scholar
- Roman J, de Arriba AF, Barron S, Michelena P, Giral M, Merlos M, Bailon E, Comalada M, Galvez J, Zarzuelo A, Ramis I: UR-1505 - a new salicylate, blocks T cell activation through nuclear factor of activated T cells. Mol Pharmacol. 2007, 72 (2): 269-279. 10.1124/mol.107.035212.PubMedView ArticleGoogle Scholar
- Bailon E, Roman J, Ramis I, Michelena P, Balsa D, Merlos M, Zarzuelo A, Galvez J, Comalada M: The new salicylate derivative UR-1505 modulates the Th2/humoral response in a dextran sodium sulphate model of colitis that resembles ulcerative colitis. J Pharmacol Sci. 2009, 109: 315-318. 10.1254/jphs.08292SC.PubMedView ArticleGoogle Scholar
- Aceves M, Duenas A, Gomez C, San Vicente E, Crespo MS, Garcia-Rodriguez C: A new pharmacological effect of salicylates: inhibition of NFAT-dependent transcription. J Immunol. 2004, 173: 5721-5729.PubMedView ArticleGoogle Scholar
- Proksch P, Giaisi M, Treiber MK, Palfi K, Merling A, Spring H, Krammer PH, Li-Weber M: Rocaglamide derivatives are immunosuppressive phytochemicals that target NF-AT activity in T cells. J Immunol. 2005, 174: 7075-7084.PubMedView ArticleGoogle Scholar
- O'Keefe SJ, Tamura J, Kincaid RL, Tocci MJ, O'Neill EA: FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature. 1992, 357: 692-694. 10.1038/357692a0.PubMedView ArticleGoogle Scholar
- Vega Lde L, Munoz E, Calzado MA, Lieb K, Candelario-Jalil E, Gschaidmeir H, Farber L, Mueller W, Stratz T, Fiebich BL: The 5-HT3 receptor antagonist tropisetron inhibits T cell activation by targeting the calcineurin pathway. Biochem Pharmacol. 2005, 70: 369-380. 10.1016/j.bcp.2005.04.031.PubMedView ArticleGoogle Scholar
- Mousavizadeh K, Rahimian R, Fakhfouri G, Aslani FS, Ghafourifar P: Anti-inflammatory effects of 5-HT receptor antagonist, tropisetron on experimental colitis in rats. Eur J Clin Invest. 2009, 39: 375-383. 10.1111/j.1365-2362.2009.02102.x.PubMedView ArticleGoogle Scholar
- Venkatesh N, Feng Y, DeDecker B, Yacono P, Golan D, Mitchison T, McKeon F: Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression. Proc Natl Acad Sci USA. 2004, 101: 8969-8974. 10.1073/pnas.0402803101.PubMed CentralPubMedView ArticleGoogle Scholar
- Baine Y, Stankunas BM, Miller P, Hobbs C, Tiberio L, Koch J, Yoon K, Sawutz D, Surowy C: Functional characterization of novel IL-2 transcriptional inhibitors. J Immunol. 1995, 154: 3667-3677.PubMedGoogle Scholar
- Yang SD, Tallant EA, Cheung WY: Calcineurin is a calmodulin-dependent protein phosphatase. Biochem Biophys Res Commun. 1982, 106: 1419-1425. 10.1016/0006-291X(82)91272-4.PubMedView ArticleGoogle Scholar
- Rusnak F, Beressi AH, Haddy A, Tefferi A: Calcineurin protein phosphatase activity in peripheral blood lymphocytes. Bone Marrow Transplant. 1996, 17: 309-313.PubMedGoogle Scholar
- Aussel C, Breittmayer JP, Pelassy C, Bernard A: Calmodulin, a junction between two independent immunosuppressive pathways in Jurkat T cells. J Biol Chem. 1995, 270: 8032-8036. 10.1074/jbc.270.14.8032.PubMedView ArticleGoogle Scholar
- Jung EJ, Hur M, Kim YL, Lee GH, Kim J, Kim I, Lee M, Han HK, Kim MS, Hwang S, et al.: Oral administration of 1, 4-aryl-2-mercaptoimidazole (KRM-III) inhibits T cell proliferation and reduces clinical severity in murine experimental autoimmune encephalomyelitis model. J Pharmacol Exp Ther. 2009,Google Scholar
- Marquez N, Sancho R, Macho A, Calzado MA, Fiebich BL, Munoz E: Caffeic acid phenethyl ester inhibits T-cell activation by targeting both nuclear factor of activated T-cells and NF-kappaB transcription factors. J Pharmacol Exp Ther. 2004, 308: 993-1001. 10.1124/jpet.103.060673.PubMedView ArticleGoogle Scholar
- Ansorge S, Reinhold D, Lendeckel U: Propolis and some of its constituents down-regulate DNA synthesis and inflammatory cytokine production but induce TGF-beta1 production of human immune cells. Z Naturforsch [C]. 2003, 58: 580-589.View ArticleGoogle Scholar
- Natarajan K, Singh S, Burke TR Jr, Grunberger D, Aggarwal BB: Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA. 1996, 93: 9090-9095. 10.1073/pnas.93.17.9090.PubMed CentralPubMedView ArticleGoogle Scholar
- Kuromitsu S, Fukunaga M, Lennard AC, Masuho Y, Nakada S: 3-(13-Hydroxytridecyl)-1-[13-(3-pyridyl)tridecyl]pyridinium chloride (YM-53792), a novel inhibitor of NF-AT activation. Biochem Pharmacol. 1997, 54: 999-1005. 10.1016/S0006-2952(97)00289-X.PubMedView ArticleGoogle Scholar
- Michne WF, Schroeder JD, Guiles JW, Treasurywala AM, Weigelt CA, Stansberry MF, McAvoy E, Shah CR, Baine Y, Sawutz DG, et al.: Novel inhibitors of the nuclear factor of activated T cells (NFAT)-mediated transcription of beta-galactosidase: potential immunosuppressive and antiinflammatory agents. J Med Chem. 1995, 38: 2557-2569. 10.1021/jm00014a009.PubMedView ArticleGoogle Scholar
- Murray CM, Hutchinson R, Bantick JR, Belfield GP, Benjamin AD, Brazma D, Bundick RV, Cook ID, Craggs RI, Edwards S, et al.: Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat Chem Biol. 2005, 1: 371-376. 10.1038/nchembio744.PubMedView ArticleGoogle Scholar
- Burres NS, Premachandran U, Hoselton S, Cwik D, Hochlowski JE, Ye Q, Sunga GN, Karwowski JP, Jackson M, Whittern DN, et al.: Simple aromatics identified with a NFAT-lacZ transcription assay for the detection of immunosuppressants. J Antibiot (Tokyo). 1995, 48: 380-386.View ArticleGoogle Scholar
- Lee SI, Kim BS, Kim KS, Lee S, Shin KS, Lim JS: Immune-suppressive activity of punicalagin via inhibition of NFAT activation. Biochem Biophys Res Commun. 2008, 371: 799-803. 10.1016/j.bbrc.2008.04.150.PubMedView ArticleGoogle Scholar
- Marquez N, Sancho R, Ballero M, Bremner P, Appendino G, Fiebich BL, Heinrich M, Munoz E: Imperatorin inhibits T-cell proliferation by targeting the transcription factor NFAT. Planta Med. 2004, 70: 1016-1021. 10.1055/s-2004-832640.PubMedView ArticleGoogle Scholar
- Jin HZ, Lee JH, Lee D, Lee HS, Hong YS, Kim YH, Lee JJ: Quinolone alkaloids with inhibitory activity against nuclear factor of activated T cells from the fruits of Evodia rutaecarpa. Biol Pharm Bull. 2004, 27: 926-928. 10.1248/bpb.27.926.PubMedView ArticleGoogle Scholar
- Kiem PV, Minh CV, Huong HT, Lee JJ, Lee IS, Kim YH: Phenolic constituents with inhibitory activity against NFAT transcription from Desmos chinensis. Arch Pharm Res. 2005, 28: 1345-1349. 10.1007/BF02977900.PubMedView ArticleGoogle Scholar
- Dat NT, Cai XF, Shen Q, Lee IS, Lee EJ, Park YK, Bae K, Kim YH: Gymnasterkoreayne G, a new inhibitory polyacetylene against NFAT transcription factor from Gymnaster koraiensis. Chem Pharm Bull (Tokyo). 2005, 53: 1194-1196. 10.1248/cpb.53.1194.View ArticleGoogle Scholar
- Dat NT, Cai XF, Shen Q, Lee IS, Kim YH: New inhibitor against nuclear factor of activated T cells transcription from Ribes fasciculatum var. chinense. Chem Pharm Bull (Tokyo). 2005, 53: 114-117. 10.1248/cpb.53.114.View ArticleGoogle Scholar
- Cai XF, Lee IS, Shen G, Dat NT, Lee JJ, Kim YH: Triterpenoids from Acanthopanax koreanum root and their inhibitory activities on NFAT transcription. Arch Pharm Res. 2004, 27: 825-828. 10.1007/BF02980173.PubMedView ArticleGoogle Scholar
- Cai XF, Lee IS, Dat NT, Shen G, Kang JS, Kim DH, Kim YH: Inhibitory lignans against NFAT transcription factor from Acanthopanax koreanum. Arch Pharm Res. 2004, 27: 738-741. 10.1007/BF02980142.PubMedView ArticleGoogle Scholar
- Cai XF, Lee IS, Dat NT, Shen G, Kim YH: Diterpenoids with inhibitory activity against NFAT transcription factor from Acanthopanax koreanum. Phytother Res. 2004, 18: 677-680. 10.1002/ptr.1523.PubMedView ArticleGoogle Scholar
- Dat NT, Lee IS, Cai XF, Shen G, Kim YH: Oleanane triterpenoids with inhibitory activity against NFAT transcription factor from Liquidambar formosana. Biol Pharm Bull. 2004, 27: 426-428. 10.1248/bpb.27.426.PubMedView ArticleGoogle Scholar
- Lee IS, Lee HK, Dat NT, Lee MS, Kim JW, Na DS, Kim YH: Lignans with inhibitory activity against NFAT transcription from Schisandra chinensis. Planta Med. 2003, 69: 63-64. 10.1055/s-2003-37024.PubMedView ArticleGoogle Scholar
- Sagoo JK, Fruman DA, Wesselborg S, Walsh CT, Bierer BE: Competitive inhibition of calcineurin phosphatase activity by its autoinhibitory domain. Biochem J. 1996, 320 (Pt 3): 879-884.PubMed CentralPubMedView ArticleGoogle Scholar
- Hashimoto Y, Perrino BA, Soderling TR: Identification of an autoinhibitory domain in calcineurin. J Biol Chem. 1990, 265: 1924-1927.PubMedGoogle Scholar
- Perrino BA, Ng LY, Soderling TR: Calcium regulation of calcineurin phosphatase activity by its B subunit and calmodulin. Role of the autoinhibitory domain. J Biol Chem. 1995, 270: 340-346. 10.1074/jbc.270.1.340.PubMedView ArticleGoogle Scholar
- Perrino BA: Regulation of calcineurin phosphatase activity by its autoinhibitory domain. Arch Biochem Biophys. 1999, 372: 159-165. 10.1006/abbi.1999.1485.PubMedView ArticleGoogle Scholar
- Terada H, Matsushita M, Lu YF, Shirai T, Li ST, Tomizawa K, Moriwaki A, Nishio S, Date I, Ohmoto T, Matsui H: Inhibition of excitatory neuronal cell death by cell-permeable calcineurin autoinhibitory peptide. J Neurochem. 2003, 87: 1145-1151. 10.1046/j.1471-4159.2003.02098.x.PubMedView ArticleGoogle Scholar
- Husain SZ, Grant WM, Gorelick FS, Nathanson MH, Shah AU: Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin. Am J Physiol Gastrointest Liver Physiol. 2007, 292: G1594-1599. 10.1152/ajpgi.00500.2006.PubMedView ArticleGoogle Scholar
- Feske S, Okamura H, Hogan PG, Rao A: Ca2+/calcineurin signalling in cells of the immune system. Biochem Biophys Res Commun. 2003, 311: 1117-1132. 10.1016/j.bbrc.2003.09.174.PubMedView ArticleGoogle Scholar
- Aramburu J, Yaffe MB, Lopez-Rodriguez C, Cantley LC, Hogan PG, Rao A: Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science. 1999, 285: 2129-2133. 10.1126/science.285.5436.2129.PubMedView ArticleGoogle Scholar
- Noguchi H, Matsushita M, Okitsu T, Moriwaki A, Tomizawa K, Kang S, Li ST, Kobayashi N, Matsumoto S, Tanaka K, et al.: A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nat Med. 2004, 10: 305-309. 10.1038/nm994.PubMedView ArticleGoogle Scholar
- Dell'Acqua ML, Dodge KL, Tavalin SJ, Scott JD: Mapping the protein phosphatase-2B anchoring site on AKAP79. Binding and inhibition of phosphatase activity are mediated by residues 315-360. J Biol Chem. 2002, 277: 48796-48802. 10.1074/jbc.M207833200.PubMed CentralPubMedView ArticleGoogle Scholar
- Lai MM, Burnett PE, Wolosker H, Blackshaw S, Snyder SH: Cain, a novel physiologic protein inhibitor of calcineurin. J Biol Chem. 1998, 273: 18325-18331. 10.1074/jbc.273.29.18325.PubMedView ArticleGoogle Scholar
- Sun L, Youn HD, Loh C, Stolow M, He W, Liu JO: Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity. 1998, 8: 703-711. 10.1016/S1074-7613(00)80575-0.PubMedView ArticleGoogle Scholar
- Harris CD, Ermak G, Davies KJ: Multiple roles of the DSCR1 (Adapt78 or RCAN1) gene and its protein product calcipressin 1 (or RCAN1) in disease. Cell Mol Life Sci. 2005, 62: 2477-2486. 10.1007/s00018-005-5085-4.PubMedView ArticleGoogle Scholar
- Chan B, Greenan G, McKeon F, Ellenberger T: Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo. Proc Natl Acad Sci USA. 2005, 102: 13075-13080. 10.1073/pnas.0503846102.PubMed CentralPubMedView ArticleGoogle Scholar
- Aubareda A, Mulero MC, Perez-Riba M: Functional characterization of the calcipressin 1 motif that suppresses calcineurin-mediated NFAT-dependent cytokine gene expression in human T cells. Cell Signal. 2006, 18: 1430-1438. 10.1016/j.cellsig.2005.11.006.PubMedView ArticleGoogle Scholar
- Martinez-Martinez S, Genesca L, Rodriguez A, Raya A, Salichs E, Were F, Lopez-Maderuelo MD, Redondo JM, de la Luna S: The RCAN carboxyl end mediates calcineurin docking-dependent inhibition via a site that dictates binding to substrates and regulators. Proc Natl Acad Sci USA. 2009, 106: 6117-6122. 10.1073/pnas.0812544106.PubMed CentralPubMedView ArticleGoogle Scholar
- Mehta S, Li H, Hogan PG, Cunningham KW: Domain architecture of the regulators of calcineurin (RCANs) and identification of a divergent RCAN in yeast. Mol Cell Biol. 2009, 29: 2777-2793. 10.1128/MCB.01197-08.PubMed CentralPubMedView ArticleGoogle Scholar
- Park S, Uesugi M, Verdine GL: A second calcineurin binding site on the NFAT regulatory domain. Proc Natl Acad Sci USA. 2000, 97: 7130-7135. 10.1073/pnas.97.13.7130.PubMed CentralPubMedView ArticleGoogle Scholar
- Liu J, Arai K, Arai N: Inhibition of NFATx activation by an oligopeptide: disrupting the interaction of NFATx with calcineurin. J Immunol. 2001, 167: 2677-2687.PubMedView ArticleGoogle Scholar
- Jang H, Cho EJ, Youn HD: A new calcineurin inhibition domain in Cabin1. Biochem Biophys Res Commun. 2007, 359: 129-135. 10.1016/j.bbrc.2007.05.066.PubMedView ArticleGoogle Scholar
- Kingsbury TJ, Cunningham KW: A conserved family of calcineurin regulators. Genes Dev. 2000, 14: 1595-1604.PubMed CentralPubMedGoogle Scholar
- Vega RB, Yang J, Rothermel BA, Bassel-Duby R, Williams RS: Multiple domains of MCIP1 contribute to inhibition of calcineurin activity. J Biol Chem. 2002, 277: 30401-30407. 10.1074/jbc.M200123200.PubMedView ArticleGoogle Scholar
- Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D'Elios MM, Telford JL, Baldari CT: The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med. 2003, 198: 1887-1897. 10.1084/jem.20030621.PubMed CentralPubMedView ArticleGoogle Scholar
- Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R: Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science. 2003, 301: 1099-1102. 10.1126/science.1086871.PubMedView ArticleGoogle Scholar
- Sundrud MS, Torres VJ, Unutmaz D, Cover TL: Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci USA. 2004, 101: 7727-7732. 10.1073/pnas.0401528101.PubMed CentralPubMedView ArticleGoogle Scholar
- Sewald X, Gebert-Vogl B, Prassl S, Barwig I, Weiss E, Fabbri M, Osicka R, Schiemann M, Busch DH, Semmrich M, et al.: Integrin subunit CD18 Is the T-lymphocyte receptor for the Helicobacter pylori vacuolating cytotoxin. Cell Host Microbe. 2008, 3: 20-29. 10.1016/j.chom.2007.11.003.PubMedView ArticleGoogle Scholar
- Miskin JE, Abrams CC, Goatley LC, Dixon LK: A viral mechanism for inhibition of the cellular phosphatase calcineurin. Science. 1998, 281: 562-565. 10.1126/science.281.5376.562.PubMedView ArticleGoogle Scholar
- Granja AG, Perkins ND, Revilla Y: A238L inhibits NF-ATc2, NF-kappa B, and c-Jun activation through a novel mechanism involving protein kinase C-theta-mediated up-regulation of the amino-terminal transactivation domain of p300. J Immunol. 2008, 180: 2429-2442.PubMedView ArticleGoogle Scholar
- Matsuda S, Shibasaki F, Takehana K, Mori H, Nishida E, Koyasu S: Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. EMBO Rep. 2000, 1: 428-434. 10.1093/embo-reports/kvd090.PubMed CentralPubMedView ArticleGoogle Scholar
- Granja AG, Nogal ML, Hurtado C, Vila V, Carrascosa AL, Salas ML, Fresno M, Revilla Y: The viral protein A238L inhibits cyclooxygenase-2 expression through a nuclear factor of activated T cell-dependent transactivation pathway. J Biol Chem. 2004, 279: 53736-53746. 10.1074/jbc.M406620200.PubMedView ArticleGoogle Scholar
- Miskin JE, Abrams CC, Dixon LK: African swine fever virus protein A238L interacts with the cellular phosphatase calcineurin via a binding domain similar to that of NFAT. J Virol. 2000, 74: 9412-9420. 10.1128/JVI.74.20.9412-9420.2000.PubMed CentralPubMedView ArticleGoogle Scholar
- Tatlock JH, Linton MA, Hou XJ, Kissinger CR, Pelletier LA, Showalter RE, Tempczyk A, Villafranca JE: Structure-based design of novel calcineurin (PP2B) inhibitors. Bioorg Med Chem Lett. 1997, 7: 1007-1012. 10.1016/S0960-894X(97)00141-8.View ArticleGoogle Scholar
- Bialojan C, Takai A: Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. Biochem J. 1988, 256: 283-290.PubMed CentralPubMedView ArticleGoogle Scholar
- Fruman DA, Klee CB, Bierer BE, Burakoff SJ: Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA. 1992, 89: 3686-3690. 10.1073/pnas.89.9.3686.PubMed CentralPubMedView ArticleGoogle Scholar
- Sinclair PJ, Wong F, Staruch MJ, Wiederrecht GJ, Parsons WH, Dumont F, Wyvratt M: Preparation and in vitro activities of naphthyl and indolyl ether derivatives of the FK-506 related immunosuppressive macrolide ascomycin. Bioorg Med Chem Lett. 1996, 6: 2193-2196. 10.1016/0960-894X(96)00398-8.View ArticleGoogle Scholar
- Baumgrass R, Weiwad M, Erdmann F, Liu JO, Wunderlich D, Grabley S, Fischer G: Reversible inhibition of calcineurin by the polyphenolic aldehyde gossypol. J Biol Chem. 2001, 276: 47914-47921.PubMedGoogle Scholar
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