TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest

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Homo sapiens
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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). 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 SFN transcription (Das et al. 2007).

Literature References
PubMed ID Title Journal Year
24096481 p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes

Manfredi, JJ, Attie, O, Aaronson, SA, Kracikova, M, Benson, EK, Sachidanandam, R, Mungamuri, SK

Oncogene 2014
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

Prieto, J, Marcaida, MJ, Montoya, G, Campos-Olivas, R, Blanco, FJ, Sánchez, R, Pantoja-Uceda, D, Diercks, T

J. Biol. Chem. 2010
23485469 A novel role for Gadd45α in base excision repair: modulation of APE1 activity by the direct interaction of Gadd45α with PCNA

Kim, HL, Kim, SU, Seo, YR

Biochem. Biophys. Res. Commun. 2013
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
15574328 DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter

Manfredi, JJ, St Clair, S, Mattia, M, Varmeh-Ziaie, S, Liu, WJ, Giono, L, DaCosta, A, Padi, A, Resnick-Silverman, L, Dastidar, J

Mol. Cell 2004
10524633 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage

Vogelstein, B, Chan, TA, Lengauer, C, Kinzler, KW, Hermeking, H

Nature 1999
7973727 Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen

Kastan, MB, Chen, IT, Gilmer, TM, Smith, ML, Chen, CY, Zhan, Q, Fornace, AJ, O'Connor, PM, Bae, I

Science 1994
15186775 Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53

Kim, J, Roeder, RG, An, W

Cell 2004
11574543 The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax

Funk, JO, Eppel, JT, Weber, HO, Samuel, T, McShea, A, Rauch, P, Verdoodt, B, Hermeking, H

J. Biol. Chem. 2001
9659898 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression

Zhang, L, Polyak, K, He, TC, Vogelstein, B, Lengauer, C, Kinzler, KW, Hermeking, H, Thiagalingam, S

Mol. Cell 1997
7784094 Characterisation of the interaction between PCNA and Gadd45

Hall, PA, Kearsey, JM, Warbrick, E, Norman, DG, Coates, PJ, Cox, LS

Oncogene 1995
16772293 Gadd45a interacts with aurora-A and inhibits its kinase activity

Zhao, Z, Dong, L, Wang, Y, Shao, S, Jin, S, Fu, M, Fan, F, Xu, N, Song, Y, Zhan, Q, Fan, W, Wang, X, Tong, T

J. Biol. Chem. 2006
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