Regulation of TP53 Degradation

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Homo sapiens
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In unstressed cells, TP53 (p53) has a short half-life as it undergoes rapid ubiquitination and proteasome-mediated degradation. The E3 ubiquitin ligase MDM2, which is a transcriptional target of TP53, plays the main role in TP53 protein down-regulation (Wu et al. 1993). MDM2 forms homodimers and homo-oligomers, but also functions as a heterodimer/hetero-oligomer with MDM4 (MDMX) (Sharp et al. 1999, Cheng et al. 2011, Huang et al. 2011, Pant et al. 2011). The heterodimers of MDM2 and MDM4 may be especially important for downregulation of TP53 during embryonic development (Pant et al. 2011).

The nuclear localization of MDM2 is positively regulated by AKT- or SGK1- mediated phosphorylation (Mayo and Donner 2001, Zhou et al. 2001, Amato et al. 2009, Lyo et al. 2010). Phosphorylation of MDM2 by CDK1 or CDK2 decreases affinity of MDM2 for TP53 (Zhang and Prives 2001). ATM and CHEK2 kinases, activated by double strand DNA breaks, phosphorylate TP53, reducing its affinity for MDM2 (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998, Chehab et al. 1999, Chehab et al. 2000). At the same time, ATM phosphorylates MDM2, preventing MDM2 dimerization (Cheng et al. 2009, Cheng et al. 2011). Both ATM and CHEK2 phosphorylate MDM4, triggering MDM2-mediated ubiquitination of MDM4 (Chen et al. 2005, Pereg et al. 2005). Cyclin G1 (CCNG1), transcriptionally induced by TP53, targets the PP2A phosphatase complex to MDM2, resulting in dephosphorylation of MDM2 at specific sites, which can have either a positive or a negative impact on MDM2 function (Okamoto et al. 2002).

In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007).

In addition to ubiquitinating MDM4 (Pereg et al. 2005), MDM2 can also undergo auto-ubiquitination (Fang et al. 2000). MDM2 and MDM4 can be deubiquitinated by the ubiquitin protease USP2 (Stevenson et al. 2007, Allende-Vega et al. 2010). The ubiquitin protease USP7 can deubiquitinate TP53, but in the presence of DAXX deubiquitinates MDM2 (Li et al. 2002, Sheng et al. 2006, Tang et al. 2006).

The tumor suppressor p14-ARF, expressed from the CDKN2A gene in response to oncogenic or oxidative stress, forms a tripartite complex with MDM2 and TP53, sequesters MDM2 from TP53, and thus prevents TP53 degradation (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005).

For review of this topic, please refer to Kruse and Gu 2009.

Literature References
PubMed ID Title Journal Year
10722742 Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53

Vousden, KH, Weissman, AM, Jensen, JP, Ludwig, RL, Fang, S

J. Biol. Chem. 2000
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
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
19816404 ATM activates p53 by regulating MDM2 oligomerization and E3 processivity

Lane, WS, Chen, L, Chen, J, Cheng, Q, Li, Z

EMBO J. 2009
16474402 Molecular recognition of p53 and MDM2 by USP7/HAUSP

Arrowsmith, CH, Duan, S, Sheng, Y, Sarkari, F, Frappier, L, Wu, T, Saridakis, V

Nat. Struct. Mol. Biol. 2006
19450511 Modes of p53 regulation

Gu, W, Kruse, JP

Cell 2009
16845383 Critical role for Daxx in regulating Mdm2

Wang, W, Zhang, J, Degenhardt, YY, Tang, J, Qu, LK, Michaelson, JS, Yang, X, El-Deiry, WS

Nat. Cell Biol. 2006
11715018 HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation

Zou, Y, Xia, W, Zhou, BP, Hung, MC, Spohn, B, Liao, Y

Nat Cell Biol 2001
19838211 MdmX is a substrate for the deubiquitinating enzyme USP2a

Allende-Vega, N, Sparks, A, Saville, MK, Lane, DP

Oncogene 2010
10570149 Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage

Halazonetis, TD, Malikzay, A, Stavridi, ES, Chehab, NH

Proc. Natl. Acad. Sci. U.S.A. 1999
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
17290220 The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2

Saville, MK, Lane, DP, Sparks, A, Xirodimas, DP, Stevenson, LF, Allende-Vega, N

EMBO J. 2007
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
11983168 Cyclin G recruits PP2A to dephosphorylate Mdm2

Taya, Y, Li, H, Jensen, MR, Prives, C, Thorgeirsson, SS, Zhang, T, Okamoto, K

Mol. Cell 2002
16163388 ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage

Lane, WS, Chen, L, Pan, Y, Chen, J, Gilkes, DM

EMBO J 2005
9733515 Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.

Appella, E, Siliciano, JD, Kastan, MB, Tamai, K, Taya, Y, Sakaguchi, K, Lim, DS, Canman, CE

Science 1998
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
8319905 The p53-mdm-2 autoregulatory feedback loop

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

Genes Dev. 1993
9733514 Enhanced phosphorylation of p53 by ATM in response to DNA damage.

Shiloh, Y, Taya, Y, Reiss, Y, Ziv, Y, Smorodinsky, NI, Prives, C, Anderson, CW, Chessa, L, Moyal, L, Shieh, S, Banin, S

Science 1998
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
15788536 Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage

Shiloh, Y, Meulmeester, E, Jochemsen, AG, Pereg, Y, Teunisse, AF, Shkedy, D, de Graaf, P, Biton, S, Lehmann, WD, Edelson-Averbukh, M, Salek, M

Proc Natl Acad Sci U S A 2005
20438709 Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway

Lyo, D, Foster, DA, Xu, L

Biochem. Biophys. Res. Commun. 2010
11359766 Cyclin a-CDK phosphorylation regulates MDM2 protein interactions

Zhang, T, Prives, C

J. Biol. Chem. 2001
9843217 ATM associates with and phosphorylates p53: mapping the region of interaction.

Gatei, M, Hobson, K, Taya, Y, Kozlov, S, Scott, S, Keating, KE, Lees-Miller, SP, Lavin, MF, Gabrielli, B, Khanna, KK, Chan, D

Nat Genet 1998
10608892 Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein

Kratowicz, SA, Sank, MJ, George, DL, Sharp, DA

J. Biol. Chem. 1999
21730163 The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo

Ganapathy, S, Wang, ZG, Liao, X, Yang, J, Li, Y, Yuan, ZM, Shadfan, M, Kawai, H, Zuo, Y, Huang, L, Yan, Z

Proc. Natl. Acad. Sci. U.S.A. 2011
11504915 A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus

Mayo, LD, Donner, DB

Proc. Natl. Acad. Sci. U.S.A. 2001
21730132 Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability

Pant, V, Quintás-Cardama, A, Iwakuma, T, Lozano, G, Xiong, S

Proc. Natl. Acad. Sci. U.S.A. 2011
10673500 Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.

Appel, M, Halazonetis, TD, Chehab, NH, Malikzay, A

Genes Dev 2000
19756449 Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation

Amato, R, Fuiano, G, Rinaldo, C, Costa, N, Soddu, S, Bellacchio, E, D'Antona, L, Mattarocci, S, Paggi, MG, Porciatti, G, Lang, F, Menniti, M, Perrotti, N, Agosti, V

J. Mol. Med. 2009
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