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. 2019 Sep 30;11(10):1475. doi: 10.3390/cancers11101475

Figure 1.

Figure 1

p53-dependent and p53-independent transcriptional regulation of p21. Chemicals, radiation, replication stress, and DNA damage induce the activity of p53. As a result, p53 activates the transcription of p21 by directly binding highly conserved p53-responsive elements (p53-RE) found in the p21 promotor. Acetylated p53 recruits TFIID subunit, TAF1, to the p53-RE on p21 in response to DNA damage. BRCA1-recruited p300/CREB-binding protein (p300/CBP) coactivator family mediates the acetylation of p53 and the activation of p21 gene. p53 recruits the histone variant H2A.Z to promote p21 transcription. p53 is phosphorylated and activated by ATM-CHK2, and ATR-CHK1 pathways in response to DNA damage. Pin1 and GADD34 promote the phosphorylation and stability of p53, and hence the transcriptional activation of p21 following DNA damage. Cell division autoantigen 1 (CDA1) inhibits MDM2, stabilizes p53, and thus promotes p21 transactivation. The histone acetyltransferase monocytic leukemia zinc finger (MOZ) directly interacts with p53 and induces the expression of p21. The proapoptotic Ras effector NORE1A induces p21 transcription by promoting p53 nuclear localization. pRb, Sp1, Sp3, and CDX2 transcription factors induce the expression of p21 in response to various stimuli, such as butyrate, phorbol myristate acetate (PMA) and nerve growth factor (NGF), independent of p53. Double homeobox 4 (Dux4) and Integrin β1 enhance the expression of p21 in a Sp1-dependent manner. Several nuclear receptors also activate p21 expression by binding to its RE, and include vitamin D receptors, retinoid receptors, and androgen receptors. The latter forms a complex with CBP/p300 and Sp1. Several other transcription factors also induce p21 and include signal transducers and activators of transcription (STAT), E2F-1/E2F-3, Smads, AP2, BETA2, GAX, CCAAT/enhancer binding protein-α (C/EBPα), C/EBPβ, and myoblast determination protein 1 (MYOD1). Importantly, p21 can be induced by TGF-β, in a p53-independent fashion, by activating Sp1 and Smads.