TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest

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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). Considering its impact on the cell cycle outcome, CDKN1A expression levels are tightly regulated. For instance, under prolonged stress, TP53 can induce the 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 has co-factors that are key determinants of transcriptional selectivity within the p53 network. For instance, 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, strongly favouring cell cycle arrest over apoptosis (Das et al. 2007).

Literature References
PubMed ID Title Journal Year
22802528 E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression

Manfredi, JJ, Tonnessen, C, Hamard, PJ, Carvajal, LA

Genes Dev. 2012
8242752 WAF1, a potential mediator of p53 tumor suppression.

Tokino, T, el-Deiry, WS, Kinzler, KW, Vogelstein, B, Lin, D, Mercer, WE, Parsons, R, Trent, JM, Velculescu, VE, Levy, DB

Cell 1993
17719541 Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation

Bernstein, A, Aaronson, SA, Kimura, Y, Raj, L, Lee, SW, Das, S, Zhao, B

Cell 2007
22802529 The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence

Lowe, SW, Aksoy, O, McCurrach, M, Wang, X, Zhao, Z, Chicas, A, Zeng, T

Genes Dev. 2012
8242751 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.

Keyomarsi, K, Elledge, SJ, Adami, GR, Wei, N, Harper, JW

Cell 1993
12692263 E2FBP1/DRIL1, an AT-rich interaction domain-family transcription factor, is regulated by p53

Ikeda, MA, Ma, K, Suganuma, T, Tamamori-Adachi, M, Ichwan, SJ, Araki, K

Mol. Cancer Res. 2003
20817677 The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability

Chen, X, Cho, SJ, Scoumanne, A, Zhang, J

Nucleic Acids Res. 2011
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

Zhu, J, Chen, X

Mol. Cell. Biol. 2000
22172947 Cooperation between ARID3A and p53 in the transcriptional activation of p21WAF1 in response to DNA damage

Ikeda, MA, Otsu, M, Lestari, W, Yamada, S, Iseki, S, Ichwan, SJ, Shimizu, S

Biochem. Biophys. Res. Commun. 2012
11812999 A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence

Douma, S, Shvarts, A, Koh, EY, Bernards, R, Daley, GQ, Brummelkamp, T, Peeper, DS

Nat. Cell Biol. 2002
9780002 A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer

Oda, K, Okuyama, S, Shirasuna, K, Okamoto, S, Suzuki, M, Sekiya, S, Nakajima, T, Hachiya, T, Nojima, H

Oncogene 1998
Orthologous Events
Cross References
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