Fig. 4
Modular architecture of p21 gene, pre-mRNA and protein, showing known functional modules (see Table 2). a The p21 gene contains: two p53-responsive elements [159, 160]; four E-box motifs for binding Transcription factor AP-4 [161]; retinoid X response [162], retinoid acid response [163] and Vitamin D response [164] elements; three STAT-binding elements that recruit STAT1, STAT3 and STAT5 dimers [165, 166]; three CDX-binding sites that bind homeobox protein CDX-2 [167]; a T-element that binds the T-box transcription factor TBX2 [168]; a binding site for CCAAT/enhancer-binding protein beta [169]; six Sp1-binding sites [170–173]; a site for binding Transcription factor AP-2-alpha [174]; sites for Transcription factor E2F1 [175]; a Forkhead-binding site for Forkhead box protein P3 [176]. b The p21 (pre-)mRNA contains: AU-rich elements in the 3′-UTR for binding ELAV-like protein 4 [177], ELAV-like protein 1 [178], and RNA-binding protein 38 [179]; a binding site for RNA-binding protein Musashi homolog 1 [180]; GC-rich sequence binding CUGBP Elav-like family member 1 and calreticulin (CRT) [148]; CU-rich sequence in the 3′-UTR for binding heterogeneous nuclear ribonucleoprotein K [181]; splice donor and acceptor site for recruitment of the spliceosome machinery for intron removal. ORF: open reading frame. c The p21 protein contains: the intrinsically disordered Cyclin-dependent Kinase Inhibitor (CKI) region [182]; a PIP degron recruiting Denticleless protein homolog [183, 184]; a D box for docking to the Cell division cycle protein 20 homolog subunit of the APC/C [185]; a PIP box for docking to the DNA polymerase delta processivity factor PCNA [142, 186]; one N-terminal and one C-terminal RxL Cyclin docking motif for binding to the Cyclin E subunit of the Cyclin E-Cdk2 kinase complex [187, 188]; an NLS for recruitment to the nuclear import machinery [189]; a modification motif for phosphorylation at T145 by PKB [190, 191]; a modification motif for phosphorylation at S146 by nuclear-Dbf2-related (NDR) kinases [192]; a modification motif for phosphorylation at S130 by Cyclin E-Cdk2 kinase complex [193, 194]