Regulation of TP53 Activity through Association with Co-factors

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Homo sapiens
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Association of TP53 (p53) with various transcriptional co-factors can promote, inhibit or provide specificity towards either transcription of cell cycle arrest genes or transcription of cell death genes. Binding of the zinc finger protein ZNF385A (HZF), which is a transcriptional target of TP53, stimulates transcription of cell cycle arrest genes, such as CDKN1A (Das et al. 2007). Binding of POU4F1 (BRN3A) to TP53 also stimulates transcription of cell cycle arrest genes while inhibiting transcription of pro-apoptotic genes (Budhram-Mahadeo et al. 1999, Hudson et al. 2005).

Binding of ASPP family proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) to TP53 stimulates transcription of pro-apoptotic TP53 targets (Samuels-Lev et al. 2001, Bergamaschi et al. 2004). Binding of the ASPP family member PPP1R13L (iASSP) inhibits TP53-mediated activation of pro-apoptotic genes probably by interfering with binding of stimulatory ASPPs to TP53 (Bergamaschi et al. 2003). Transcription of pro-apoptotic genes is also stimulated by binding of TP53 to POU4F2 (BRN3B) (Budrham-Mahadeo et al. 2006, Budhram-Mahadeo et al. 2014) or to hCAS/CSE1L (Tanaka et al. 2007).

Binding of co-factors to TP53 can also affect protein stability. For example, PHF20 binds to TP53 dimethylated on lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s) and interferes with MDM2 binding, resulting in prolonged TP53 half-life (Cui et al. 2012). Long noncoding RNAs can contribute to p53-dependent transcriptional responses (Huarte et al. 2010). For a general review on this topic, see Espinosa 2008, Beckerman and Prives 2010, Murray-Zmijewski et al. 2008, An et al. 2004 and Barsotti and Prives 2010.

Literature References
PubMed ID Title Journal Year
15598651 Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate

Latchman, DS, Hudson, CD, Morris, PJ, Budhram-Mahadeo, VS

J. Biol. Chem. 2005
12524540 iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human

Kuwabara, PE, Hsieh, JK, Samuels, Y, Zhong, S, Trigiante, G, Lu, X, Campargue, I, O'Connor, DJ, Bergamaschi, D, Tomlinson, ML, O'Neil, NJ, Crook, T

Nat. Genet. 2003
11684014 ASPP proteins specifically stimulate the apoptotic function of p53

Hsieh, JK, Trigiante, G, Crook, T, Zhong, S, Bergamaschi, D, O'Connor, DJ, Lu, X, Campargue, I, Naumovski, L, Samuels-Lev, Y

Mol. Cell 2001
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
15186775 Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53

Kim, J, Roeder, RG, An, W

Cell 2004
20673990 A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response

Khalil, AM, Attardi, LD, Amit, I, Koziol, MJ, Kenzelmann-Broz, D, Rabani, M, Guttman, M, Regev, A, Jacks, T, Zuk, O, Feldser, D, Garber, M, Rinn, JL, Lander, ES, Huarte, M

Cell 2010
10329733 p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor

Budhram-Mahadeo, V, Boxer, LM, Midgley, CA, Morris, PJ, Smith, MD, Latchman, DS

J. Biol. Chem. 1999
17719542 hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes

Tanaka, T, Tatsuno, I, Prives, C, Ohkubo, S

Cell 2007
20679336 Transcriptional regulation by p53

Beckerman, R, Prives, C

Cold Spring Harb Perspect Biol 2010
18278067 Mechanisms of regulatory diversity within the p53 transcriptional network

Espinosa, JM

Oncogene 2008
17145718 Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression

Latchman, DS, Ensor, E, Lee, S, Perez-Sanchez, C, Morris, PJ, Bowen, S, Budhram-Mahadeo, VS

Nucleic Acids Res. 2006
25356872 Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults

Fujita, R, Budhram-Mahadeo, V, Bitsi, S, Heads, R, Sicard, P

Cell Death Dis 2014
20691894 Noncoding RNAs: the missing "linc" in p53-mediated repression

Barsotti, AM, Prives, C

Cell 2010
14729977 ASPP1 and ASPP2: common activators of p53 family members

Samuels, Y, Lu, X, Jin, B, Duraisingham, S, Bergamaschi, D, Crook, T

Mol. Cell. Biol. 2004
18719709 A complex barcode underlies the heterogeneous response of p53 to stress

Slee, EA, Murray-Zmijewski, F, Lu, X

Nat. Rev. Mol. Cell Biol. 2008
22864287 PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53

Cui, G, Mer, G, Kaneko, S, Badeaux, AI, Park, S, Yan, F, Bedford, MT, Thompson, JR, Lee, J, Botuyan, MV, Yuan, Z, Cheng, JQ, Kim, D

Nat. Struct. Mol. Biol. 2012
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