Reactome | Regulation of TP53 Expression and Degradation

Regulation of TP53 Expression and Degradation

Stable Identifier

R-HSA-6806003

Type

Pathway

Species

Homo sapiens

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Regulation of TP53 Expression and Degradation

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TP53 (p53) tumor suppressor protein is a transcription factor that functions as a homotetramer (Jeffrey et al. 1995). The protein levels of TP53 are low in unstressed cells due to MDM2-mediated ubiquitination that triggers proteasome-mediated degradation of TP53 (Wu et al. 1993). The E3 ubiquitin ligase MDM2 functions as a homodimer/homo-oligomer or a heterodimer/hetero-oligomer with MDM4 (MDMX) (Linares et al. 2003, Toledo and Wahl 2007, Cheng et al. 2011, Wade et al. 2013).

Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).

While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005).

Literature References

PubMed ID	Title	Journal	Year
11883935	Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors Parisi, T, Pollice, A, Di Cristofano, A, Calabrò, V, La Mantia, G	Biochem. Biophys. Res. Commun.	2002
15103385	The ubiquitin ligase COP1 is a critical negative regulator of p53 Dornan, D, Wertz, I, Shimizu, H, Arnott, D, Frantz, GD, Dowd, P, O'Rourke, K, Koeppen, H, Dixit, VM	Nature	2004
17121812	CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation Yang, W, Rozan, LM, McDonald, ER, Navaraj, A, Liu, JJ, Matthew, EM, Wang, W, Dicker, DT, El-Deiry, WS	J. Biol. Chem.	2007
9529249	ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways Zhang, Y, Xiong, Y, Yarbrough, WG	Cell	1998
7878469	Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms Jeffrey, PD, Gorina, S, Pavletich, NP	Science	1995
12654245	Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation Leng, RP, Lin, Y, Ma, W, Wu, H, Lemmers, B, Chung, S, Parant, JM, Lozano, G, Hakem, R, Benchimol, S	Cell	2003
23303139	MDM2, MDMX and p53 in oncogenesis and cancer therapy Wade, M, Li, YC, Wahl, GM	Nat. Rev. Cancer	2013
8319905	The p53-mdm-2 autoregulatory feedback loop Wu, X, Bayle, JH, Olson, D, Levine, AJ	Genes Dev.	1993
21986495	Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage Cheng, Q, Cross, B, Li, B, Chen, L, Li, Z, Chen, J	Mol. Cell. Biol.	2011
19250907	Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage Mahmoudi, S, Henriksson, S, Corcoran, M, Méndez-Vidal, C, Wiman, KG, Farnebo, M	Mol. Cell	2009
11923872	Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization Li, M, Chen, D, Shiloh, A, Luo, J, Nikolaev, AY, Qin, J, Gu, W	Nature	2002
17499002	MDM2 and MDM4: p53 regulators as targets in anticancer therapy Toledo, F, Wahl, GM	Int. J. Biochem. Cell Biol.	2007
16213212	Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin Takagi, M, Absalon, MJ, McLure, KG, Kastan, MB	Cell	2005
21814038	Transcriptional and epigenetic regulation of the p53 tumor suppressor gene Saldaña-Meyer, R, Recillas-Targa, F	Epigenetics	2011
19293287	MicroRNA-125b is a novel negative regulator of p53 Le, MT, Teh, C, Shyh-Chang, N, Xie, H, Zhou, B, Korzh, V, Lodish, HF, Lim, B	Genes Dev.	2009
15563468	MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1 Voncken, JW, Niessen, H, Neufeld, B, Rennefahrt, U, Dahlmans, V, Kubben, N, Holzer, B, Ludwig, S, Rapp, UR	J. Biol. Chem.	2005