TP53 Regulates Transcription of Cell Cycle Genes

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Under a variety of stress conditions, TP53 (p53), stabilized by stress-induced phosphorylation at least on S15 and S20 serine residues, can induce the transcription of genes involved in cell cycle arrest. Cell cycle arrest provides cells an opportunity to repair the damage before division, thus preventing the transmission of genetic errors to daughter cells. In addition, it allows cells to attempt a recovery from the damage and survive, preventing premature cell death.

TP53 controls transcription of genes involved in both G1 and G2 cell cycle arrest. The most prominent TP53 target involved in G1 arrest is the inhibitor of cyclin-dependent kinases CDKN1A (p21). CDKN1A is one of the earliest genes induced by TP53 (El-Deiry et al. 1993). CDKN1A binds and inactivates CDK2 in complex with cyclin A (CCNA) or E (CCNE), thus preventing G1/S transition (Harper et al. 1993). Nevertheless, under prolonged stress, the cell destiny may be diverted towards an apoptotic outcome. For instance, in case of an irreversible damage, TP53 can induce transcription of an RNA binding protein PCBP4, which can bind and destabilize CDKN1A mRNA, thus alleviating G1 arrest and directing the affected cell towards G2 arrest and, possibly, apoptosis (Zhu and Chen 2000, Scoumanne et al. 2011). Expression of E2F7 is directly induced by TP53. E2F7 contributes to G1 cell cycle arrest by repressing transcription of E2F1, a transcription factor that promotes expression of many genes needed for G1/S transition (Aksoy et al. 2012, Carvajal et al. 2012). ARID3A is a direct transcriptional target of TP53 (Ma et al. 2003) that may promote G1 arrest by cooperating with TP53 in induction of CDKN1A transcription (Lestari et al. 2012). However, ARID3A may also promote G1/S transition by stimulating transcriptional activity of E2F1 (Suzuki et al. 1998, Peeper et al. 2002).

TP53 contributes to the establishment of G2 arrest by inducing transcription of GADD45A and SFN, and by inhibiting transcription of CDC25C. TP53 induces GADD45A transcription in cooperation with chromatin modifying enzymes EP300, PRMT1 and CARM1 (An et al. 2004). GADD45A binds Aurora kinase A (AURKA), inhibiting its catalytic activity and preventing AURKA-mediated G2/M transition (Shao et al. 2006, Sanchez et al. 2010). GADD45A also forms a complex with PCNA. PCNA is involved in both normal and repair DNA synthesis. The effect of GADD45 interaction with PCNA, if any, on S phase progression, G2 arrest and DNA repair is not known (Smith et al. 1994, Hall et al. 1995, Sanchez et al. 2010, Kim et al. 2013). SFN (14-3-3-sigma) is induced by TP53 (Hermeking et al. 1997) and contributes to G2 arrest by binding to the complex of CDK1 and CCNB1 (cyclin B1) and preventing its translocation to the nucleus. Phosphorylation of a number of nuclear proteins by the complex of CDK1 and CCNB1 is needed for G2/M transition (Chan et al. 1999). While promoting G2 arrest, SFN can simultaneously inhibit apoptosis by binding to BAX and preventing its translocation to mitochondria, a step involved in cytochrome C release (Samuel et al. 2001). TP53 binds the promoter of the CDC25C gene in cooperation with the transcriptional repressor E2F4 and represses CDC25C transcription, thus maintaining G2 arrest (St Clair et al. 2004, Benson et al. 2014).

Several direct transcriptional targets of TP53 are involved in cell cycle arrest but their mechanism of action is still unknown. BTG2 is induced by TP53, leading to cessation of cellular proliferation (Rouault et al. 1996, Duriez et al. 2002). BTG2 binds to the CCR4-NOT complex and promotes mRNA deadenylation activity of this complex. Interaction between BTG2 and CCR4-NOT is needed for the antiproliferative activity of BTG2, but the underlying mechanism has not been elucidated (Rouault et al. 1998, Mauxion et al. 2008, Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012). Two polo-like kinases, PLK2 and PLK3, are direct transcriptional targets of TP53. TP53-mediated induction of PLK2 may be important for prevention of mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is involved in the regulation of centrosome duplication through phosphorylation of centrosome-related proteins CENPJ (Chang et al. 2010) and NPM1 (Krause and Hoffmann 2010). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006). Induction of PLK3 transcription by TP53 (Jen and Cheung 2005) may be important for coordination of M phase events through PLK3-mediated nuclear accumulation of CDC25C (Bahassi et al. 2004). RGCC is induced by TP53 and implicated in cell cycle regulation, possibly through its association with PLK1 (Saigusa et al. 2007). PLAGL1 (ZAC1) is a zinc finger protein directly transcriptionally induced by TP53 (Rozenfeld-Granot et al. 2002). PLAGL1 expression is frequently lost in cancer (Varrault et al. 1998) and PLAGL1 has been implicated in both cell cycle arrest and apoptosis (Spengler et al. 1997), but its mechanism of action remains unknown.

The zinc finger transcription factor ZNF385A (HZF) is a direct transcriptional target of TP53 that can form a complex with TP53 and facilitate TP53-mediated induction of CDKN1A and SFN (14-3-3 sigma) transcription (Das et al. 2007).

For a review of the role of TP53 in cell cycle arrest and cell cycle transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

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