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Table 1 TNFR1 model A

From: A systems biology approach to suppress TNF-induced proinflammatory gene expressions

  Reaction Formula and parameters (s-1) Remarks
1 1 TNFR1 TRADD k 1 * TNFR1 k 1 = 5e-3 Activation of TRADD by TNFR1
2 2 TRADD cIAP1/2 k 2 * TRADD k 2 = 2e-2 Formation of Complex 1 containing TRADD, cIAP1/2, TRAF2, TRAF5, RIP1 and the TAB/TAK complex
3 3 cIAP1/2 TRAF2 k 3 * cIAP1/2 k 3 = 1e-2
4 4 cIAP1/2 TRAF5 k 4 * cIAP1/2 k 4 = 8e-3
5 5 TRAF2 RIP1 k 5 * TRAF2 k 5 = 1e-3
6 5 TRAF5 RIP1 k 6 * TRAF5 k 6 = 1e-3
7 6 TRADD TRAF6 k 7 * TRADD k 7 = 2e-2 Activation of TRAF6 by TRADD
8 5 TRAF6 RIP1 k 8 * TRAF6 k 8 = 1e-4 Activation of RIP1 and TAK1 complex by TRAF6
9 7 TRAF6 TAK1 complex k 9 * TRAF6 k 9 = 1.3e-4
10 8 RIP1 LUBAC k 10 * RIP1 k 10 = 7e-3 Complex 1 ubiquitination by LUBAC and SHARPIN
11 9 RIP1 SHARPIN k 11 * RIP1 k 11 = 7e-3
12 7 LUBAC TAK1 complex k 12 * LUBAC k 12 = 1e-1
13 SHARPIN IKK complex k 13 * SHARPIN k 13 = 1e-2 Activation of IKK complex by Complex 1
14 TAK1 complex IKK complex k 14 * TAK1 complex k 14 = 1e-1
15 10 IKK complex IκBα k 15 * IKK complex k 15 = 1e-2 Phosphorylation of IκBα by IKK
16 IκBα NF-κBc k 16 * IκBα k 16 = 8e-3 Degradation of IκBα forms NF-κB
17 NF-κBc NF-κBn k 17 * NF-κBc k 17 = 1.7e-2 Translocation of NF-κB to nucleus
18 TAK1 complex MKK1/2 k 18 * TAK1 complex k 18 = 1.5e-3 Activation of MAP kinases kinases by TAK1 complex
19 11 TAK1 complex MKK3/6 k 19 * TAK1 complex k 19 = 1e-2
20 TAK1 complex MKK4/7 k 20 * TAK1 complex k 20 = 1e-2
21 MKK1/2 ERK k 21 * MKK1/2 k 21 = 5e-3 Activation of MAP kinases
22 12 MKK3/6 p38 k 22 * MKK3/6 k 22 = 5e-3
24 MKK4/7 JNK k 23 * MKK4/7 k 23 = 5e-3
24 p38 p38n k 24 * p38 k 24 = 5e-2 Translocation of MAP kinases into nucleus
25 JNK JNKn k 25 * JNK k 25 = 5e-2
26 ERK ERKn k 26 * ERK k 26 = 5e-3
27 p38n AP1 k 27 * p38n k 27 = 1e-2 Activation of AP1 by MAP kinases
28 ERKn AP1 k 28 * ERKn k 28 = 1e-2
29 JNKn AP1 k 29 * JNKn k 29 = 1e-2
30 AP1 GI promoter k 30 * AP1 k 30 = 1e-1 Promoter binding of AP1 and NF-κB for group I genes
31 NF-κBn GI promoter k 31 * NF-κBn k 31 = 5e-3
32 G1 promoter GI pre-mRNA k 32 * GI promoter k 32 = 1e-2 Group I genes transcription, splicing (1 step) and decay
33 GI pre-mRNA GI mRNA k 33 * GI pre-mRNA k 33 = 5e-2
34 GI mRNA GI mRNA decay k 34 * GI mRNA k 34 = 2e-3
35 13 AP1 GII promoter k 35 * AP1 k 35 = 1.1e-2 Promoter binding of AP1 and NF-κB for group II genes
36 NF-κBn GII promoter k 36 * NF-κBn k 36 = 4e-3
37 GII promoter GII pre-mRNA/1 k 37 * GII promoter k 37 = 2e-3 Group II genes transcription, splicing (2 steps) and decay
38 GII pre-mRNA/1 GII pre-mRNA/2 k 38 * GII pre-mRNA/1 k 38 = 5e-2
39 GII pre-mRNA/2 GII mRNA k 39 * GII pre-mRNA/2 k 39 = 5e-2
40 13 GII mRNA GII mRNA decay k 40 * GII mRNA k 40 = 1.2e-4
41 AP1 GIII promoter k 41 * AP1 k 41 = 5e-3 Promoter binding of AP1 and NF-κB for group III genes
42 NF-κBn GIII promoter k 42 * NF-κBn k 42 = 1e-4
43 GIII promoter GIII pre-mRNA/1 k 43 * GIII promoter k 43 = 1e-1 Group III genes transcription, splicing (3 steps) and decay
44 GIII pre-mRNA/1 GIII pre-mRNA/2 k 44 * GIII pre-mRNA/1 k 44 = 4e-4
45 GIII pre-mRNA/2 GIII pre-mRNA/3 k 45 * GIII pre-mRNA/2 k 45 = 1e-3
46 GIII pre-mRNA/3 GIII mRNA k 46 * GIII pre-mRNA/3 k 46 = 2e-4
47 GIII mRNA GIII mRNA decay k 47 * GIII mRNA k 47 = 2e-5
48 GI mRNA X1 k 48 * GI mRNA k 48 = 1e-5 Feedback processes via group I genes or NF-κB
49 NF-κBn X1 k 49 * NF-κBn k 49 = 5e-1 Steps of the secondary feedback processes (cytosolic or autocrine signaling):
50 X1 X2 k 50 * X1 k 50 = 2e-3
51 X2 X3 k 51 * X2 k 51 = 2e-3
52 X3 X4 k 52 * X3 k 52 = 2e-3
53 X4 X5 k 53 * X4 k 53 = 2e-3
54 X5 X6 k 54 * X5 k 54 = 2e-3
55 X6 X7 k 55 * X6 k 55 = 2e-3 • expression (e.g. translation)
56 X7 X8 k 56 * X7 k 56 = 2e-3 • transport (e.g. secretion)
57 X8 X9 k 57 * X8 k 57 = 2e-3 • signaling (e.g. receptor binding, activation of transcription factors)
58 X9 X10 k 58 * X9 k 58 = 2e-3
59 X10 X11 k 59 * X10 k 59 = 2e-3
60 X11 X12 k 60 * X11 k 60 = 2e-3
61 X12 X13 k 61 * X12 k 61 = 2e-3
62 X13 X14 k 62 * X13 k 62 = 2e-3
63 X14 IκBα k 63 * X14 k 63 = 2e-3 IκBα feedback activation
64 X14 Y k 64 * X14 k 64 = 1e-5 Group III feedback activation via transcription factor Y
65 Y GIII promoter k 65 * Y k 65 = 2e-3
  1. (1–12): in-silico knock-out conditions are performed by setting parameter values (k i ) to 0 for targeted reactions in TRADD KO (1), cIAP1/2 KO (2), TRAF2 KO (3), TRAF5 KO (4) TRAF2/5 DKO (3,4), RIP KO (5), TRAF6 KO (6), TAK1 complex KO (7), LUBAC KO (8), SHARPIN KO (9), IκBα KO (10), MKK3/6 KO (11) and p38 KO (12). (13) Kinetics of Group II mRNA transcription and decay processes were refitted after adding feedback (without feedback: k 35 = 7e-3, k 40 = 1.2e-5). Bold italic fonts (reactions 48–65) indicate additional feedback activation pathways required for group III continuous activation. * indicates the multiplication sign.