TP53 Regulates Transcription of Cell Cycle Genes

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.<p>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).<p>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).<p>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.<p>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).<p>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.

在多种应激条件下，通过应激诱导的磷酸化稳定在至少S15和S20丝氨酸残基上的TP53（p53），能够诱导参与细胞周期停滞的基因转录。细胞周期停滞为细胞提供了在分裂前修复损伤的机会，从而防止遗传错误传递至子细胞。此外，它还允许细胞尝试从损伤中恢复并存活，防止细胞过早死亡。TP53控制参与G1和G2细胞周期停滞的基因转录。在G1停滞中，最突出的TP53靶点是周期依赖性激酶抑制剂CDKN1A（p21）。CDKN1A是TP53诱导的最早基因之一（El-Deiry等，1993年）。CDKN1A与周期蛋白A（CCNA）或E（CCNE）形成复合物并失活CDK2，从而防止G1/S转换（Harper等，1993年）。然而，在长期应激下，细胞命运可能转向凋亡结局。例如，在不可逆损伤的情况下，TP53可以诱导RNA结合蛋白PCBP4的转录，该蛋白可以结合并去稳定CDKN1A mRNA，从而缓解G1停滞并指导受影响的细胞向G2停滞甚至凋亡转变（Zhu和Chen，2000年，Scoumanne等，2011年）。E2F7的转录直接被TP53诱导。E2F7通过抑制E2F1的转录，即促进G1/S转换所需基因表达的转录因子，从而有助于G1细胞周期停滞（Aksoy等，2012年，Carvajal等，2012年）。ARID3A是TP53的直接转录靶标（Ma等，2003年），它可能通过协同TP53诱导CDKN1A转录来促进G1停滞（Lestari等，2012年）。然而，ARID3A也可能通过刺激E2F1的转录活性来促进G1/S转换（Suzuki等，1998年，Peeper等，2002年）。TP53通过诱导GADD45A和SFN（14-3-3-sigma）的转录以及抑制CDC25C的转录，对建立G2停滞作出贡献。TP53与组蛋白修饰酶EP300、PRMT1和CARM1合作，诱导GADD45的转录（An等，2004年）。GADD45与PCNA形成复合物。PCNA参与正常和修复DNA合成。GADD45与PCNA相互作用对S期进程、G2停滞和DNA修复的影响尚不清楚（Smith等，1994年，Hall等，1995年，Sanchez等，2010年，Kim等，2013年）。SFN（14-3-3-sigma）由TP53诱导（Hermeking等，1997年）并通过与CDK1和CCNB1（周期蛋白B1）复合物结合，防止其转移到细胞核中，从而有助于G2停滞。CDK1和CCNB1复合物通过磷酸化大量核蛋白，对于G2/M转换至关重要（Chan等，1999年）。在促进G2停滞的同时，SFN可以通过与BAX结合并防止其转移到线粒体中，从而抑制细胞凋亡，这是细胞色素C释放的步骤（Samuel等，2001年）。TP53与转录抑制因子E2F4合作，结合CDC25C基因启动子，抑制CDC25C的转录，从而维持G2停滞（St Clair等，2004年，Benson等，2014年）。TP53的几个直接转录靶标参与细胞周期停滞，但它们的作用机制尚不清楚。BTG2由TP53诱导，导致细胞增殖停止（Rouault等，1996年，Duriez等，2002年）。BTG2与CCR4-NOT复合物结合并促进该复合物的mRNA去腺苷酸化活性。BTG2与CCR4-NOT之间的相互作用对于BTG2的抗增殖活性是必需的，但其潜在机制尚未阐明（Rouault等，1998年，Mauxion等，2008年，Horiuchi等，2009年，Doidge等，2012年，Ezzeddine等，2012年）。两种 Polo样激酶PLK2和PLK3是TP53的直接转录靶标。TP53介导的PLK2诱导对于防止纺锤体损伤后的有丝分裂灾难可能很重要（Burns等，2003年）。PLK2通过磷酸化与中心体相关的蛋白CENPJ（Chang等，2010年）和NPM1（Krause和Hoffmann，2010年）来调节中心体复制。PLK2在B细胞恶性肿瘤中经常通过启动子甲基化被转录沉默（Syed等，2006年）。TP53诱导PLK3转录可能对于通过PLK3介导的CDC25C的核积累来协调M期事件很重要（Bahassi等，2004年）。RGCC由TP53诱导，并涉嫌参与细胞周期调节，可能通过其与PLK1的关联（Saigusa等，2007年）。PLAGL1（ZAC1）是一种锌指蛋白，由TP53直接转录诱导（Rozenfeld-Granot等，2002年）。PLAGL1的表达在癌症中经常丢失（Varrault等，1998年），PLAGL1已涉嫌参与细胞周期停滞和凋亡（Spengler等，1997年），但其作用机制尚不清楚。《锌指转录因子ZNF385A（HZF）是TP53的直接转录靶标，可以与TP53形成复合物，并促进TP53介导的CDKN1A和SFN（14-3-3 sigma）转录》（Das等，2007年）。关于TP53在细胞周期停滞中的作用及其细胞周期转录靶标的综述，请参阅Riley等（2008年）、Murray-Zmijewski等（2008年）、Bieging等（2014年）、Kruiswijk等（2015年）。