Reactome: A Curated Pathway Database

TP53 Regulates Transcription of Cell Cycle Genes

Stable Identifier
R-HSA-6791312
Type
Pathway
Species
Homo sapiens
Locations in the PathwayBrowser
Summation

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.

Literature References
PubMed ID Title Journal Year
11814693 The human BTG2/TIS21/PC3 gene: genomic structure, transcriptional regulation and evaluation as a candidate tumor suppressor gene Gene 2002
24739573 Unravelling mechanisms of p53-mediated tumour suppression Nat. Rev. Cancer 2014
22802528 E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression Genes Dev. 2012
14968113 Cdc25C phosphorylation on serine 191 by Plk3 promotes its nuclear translocation Oncogene 2004
11896574 A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1 Oncogene 2002
23236473 The anti-proliferative activity of BTG/TOB proteins is mediated via the Caf1a (CNOT7) and Caf1b (CNOT8) deadenylase subunits of the Ccr4-not complex PLoS ONE 2012
12897130 Silencing of the novel p53 target gene Snk/Plk2 leads to mitotic catastrophe in paclitaxel (taxol)-exposed cells Mol. Cell. Biol. 2003
18719709 A complex barcode underlies the heterogeneous response of p53 to stress Nat. Rev. Mol. Cell Biol. 2008
12692263 E2FBP1/DRIL1, an AT-rich interaction domain-family transcription factor, is regulated by p53 Mol. Cancer Res. 2003
18431400 Transcriptional control of human p53-regulated genes Nat. Rev. Mol. Cell Biol. 2008
9712883 Interaction of BTG1 and p53-regulated BTG2 gene products with mCaf1, the murine homolog of a component of the yeast CCR4 transcriptional regulatory complex J. Biol. Chem. 1998
18337750 The BTG2 protein is a general activator of mRNA deadenylation EMBO J. 2008
19276069 Structural basis for the antiproliferative activity of the Tob-hCaf1 complex J. Biol. Chem. 2009
22252318 Evidence providing new insights into TOB-promoted deadenylation and supporting a link between TOB's deadenylation-enhancing and antiproliferative activities Mol. Cell. Biol. 2012
11574543 The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax J. Biol. Chem. 2001
9671765 hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer Proc. Natl. Acad. Sci. U.S.A. 1998
15186775 Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53 Cell 2004
17719541 Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation Cell 2007
8242752 WAF1, a potential mediator of p53 tumor suppression. Cell 1993
9184226 Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain EMBO J. 1997
16160013 Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies Blood 2006
24096481 p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes Oncogene 2014
11812999 A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence Nat. Cell Biol. 2002
16772293 Gadd45a interacts with aurora-A and inhibits its kinase activity J. Biol. Chem. 2006
7784094 Characterisation of the interaction between PCNA and Gadd45 Oncogene 1995
20531387 PLK2 phosphorylation is critical for CPAP function in procentriole formation during the centrosome cycle EMBO J. 2010
10891498 MCG10, a novel p53 target gene that encodes a KH domain RNA-binding protein, is capable of inducing apoptosis and cell cycle arrest in G(2)-M Mol. Cell. Biol. 2000
8242751 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993
22802529 The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence Genes Dev. 2012
7973727 Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen Science 1994
15574328 DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter Mol. Cell 2004
20352051 Polo-like kinase 2-dependent phosphorylation of NPM/B23 on serine 4 triggers centriole duplication PLoS ONE 2010
23485469 A novel role for Gadd45? in base excision repair: modulation of APE1 activity by the direct interaction of Gadd45? with PCNA Biochem. Biophys. Res. Commun. 2013
20460379 Solution structure of human growth arrest and DNA damage 45alpha (Gadd45alpha) and its interactions with proliferating cell nuclear antigen (PCNA) and Aurora A kinase J. Biol. Chem. 2010
17146433 RGC32, a novel p53-inducible gene, is located on centrosomes during mitosis and results in G2/M arrest Oncogene 2007
9780002 A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer Oncogene 1998
9659898 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression Mol. Cell 1997
22172947 Cooperation between ARID3A and p53 in the transcriptional activation of p21WAF1 in response to DNA damage Biochem. Biophys. Res. Commun. 2012
8944033 Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway Nat. Genet. 1996
20817677 The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability Nucleic Acids Res. 2011
16140933 Identification of novel p53 target genes in ionizing radiation response Cancer Res. 2005
26122615 p53 in survival, death and metabolic health: a lifeguard with a licence to kill Nat. Rev. Mol. Cell Biol. 2015
10524633 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage Nature 1999
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