Regulation of TP53 Expression and Degradation

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Homo sapiens
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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
15103385 The ubiquitin ligase COP1 is a critical negative regulator of p53

Dowd, P, Koeppen, H, Dornan, D, Wertz, I, Frantz, GD, O'Rourke, K, Shimizu, H, Dixit, VM, Arnott, D

Nature 2004
11883935 Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors

Parisi, T, Calabrò, V, La Mantia, G, Pollice, A, Di Cristofano, A

Biochem. Biophys. Res. Commun. 2002
17121812 CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation

Dicker, DT, Wang, W, Liu, JJ, McDonald, ER, Navaraj, A, Yang, W, El-Deiry, WS, Matthew, EM, Rozan, LM

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

Pavletich, NP, Jeffrey, PD, Gorina, S

Science 1995
12654245 Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation

Lemmers, B, Hakem, R, Leng, RP, Lozano, G, Ma, W, Wu, H, Benchimol, S, Chung, S, Parant, JM, Lin, Y

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

Levine, AJ, Olson, D, Bayle, JH, Wu, X

Genes Dev. 1993
21986495 Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage

Chen, L, Chen, J, Cheng, Q, Li, B, Cross, B, Li, Z

Mol. Cell. Biol. 2011
19250907 Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage

Méndez-Vidal, C, Farnebo, M, Henriksson, S, Mahmoudi, S, Wiman, KG, Corcoran, M

Mol. Cell 2009
11923872 Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization

Gu, W, Luo, J, Nikolaev, AY, Shiloh, A, Chen, D, Qin, J, Li, M

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, Kastan, MB, McLure, KG

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

Teh, C, Lim, B, Lodish, HF, Zhou, B, Shyh-Chang, N, Le, MT, Xie, H, Korzh, V

Genes Dev. 2009
15563468 MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1

Ludwig, S, Voncken, JW, Neufeld, B, Kubben, N, Niessen, H, Dahlmans, V, Rennefahrt, U, Holzer, B, Rapp, UR

J. Biol. Chem. 2005
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