Unlocking the Mdm2-p53 loop: Ubiquitin is the key

Clegg, Hilary V.; Itahana, Koji; Zhang, Yanping

doi:10.4161/cc.7.3.5358

Cited by 59 publications

(50 citation statements)

References 43 publications

(60 reference statements)

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“…94 Recent genetic data suggest, however, that endogenous Mdm2 does not regulate its own stability by self-ubiquitylation. 95 Mdm2 steady-state levels observed in mice in which the RING E3 ubiquitin ligase activity of Mdm2 was abrogated by a single-point mutation were comparable with the levels in wild-type mice, implying that Mdm2 stability is controlled by another E3 ubiquitin ligase in vivo. The histone acetyltransferase PCAF (p300-CBP-associated factor) has recently been proposed as a putative candidate 96 as knockdown of PCAF in U2OS and HeLa cancer cell lines stabilized Mdm2.…”

Section: Regulation Of Mdm2-mediated P53 Ubiquitylationmentioning

confidence: 68%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

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The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into Mdm2-mediated regulation of p53 and how the physical and functional interactions between these two proteins are regulated. Moreover, a p53-independent role of Mdm2 has recently been confirmed by genetic data. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this review.

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Section: Regulation Of Mdm2-mediated P53 Ubiquitylationmentioning

confidence: 68%

Mdm2-mediated ubiquitylation: p53 and beyond

2009

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“…The first class describes E3 ligases that can promote both mono-and polyubiquitination and thereby evoke differential functional consequences such as changes in subcellular localization, inhibition of DNA binding, or targeting for proteasomal degradation. Thus far, Mdm2 is the only p53-specific E3 ligase that has been found able to perform such differential regulation (4,12,67). Based on their ability to target p53 for degradation by polyubiquitination, ARF-BP1, COP-1, and Pirh2 comprise the second group of E3 ligases (4).…”

Section: Discussionmentioning

confidence: 99%

MSL2 Promotes Mdm2-independent Cytoplasmic Localization of p53

Kruse

2009

Journal of Biological Chemistry

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Although it was originally thought of as a passive way to block the nuclear function of p53, accumulating evidence suggests that cytoplasmic localization of p53 plays an active role in p53-mediated functions such as apoptosis and autophagy. Previous studies by us and others demonstrated that Mdm2-mediated p53 ubiquitination induces both degradation and cytoplasmic localization. Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization.The function of the tumor suppressor p53 as a sequencespecific transcription factor controlling the expression of numerous target genes is critical for the regulation of cellular senescence, cell-cycle arrest, and apoptosis (1-3). During normal homeostasis, p53 is localized predominantly in the nucleus and is maintained at low levels via ubiquitination-mediated targeting for proteasomal degradation (4). Both protein levels and transcriptional activity increase dramatically in response to stress through an array of critical post-translational modifications (4, 5). Polyubiquitination of C-terminal lysines of p53 by Mdm2 (6 -8) and other ubiquitin-protein isopeptide ligases (E3) 2 such as Pirh2 (9), COP-1 (10), and Arf-BP1 (11) controls p53 levels by targeting p53 for proteasomal degradation in unstressed cells or after the cellular stress is resolved (4, 12). The stress-induced p53-dependent apoptotic response consists of transcription-dependent and -independent functions of p53 (13-17). Although transactivation of pro-apoptotic target genes such as PUMA, BAX, and PIG3 requires p53 to act as a transcription factor in the nucleus, cytoplasmic p53 can elicit an apoptotic response by localizing to the mitochondria and activating a direct mitochondrial death program (13, 18 -26). Mdm2-mediated p53 monoubiquitination, occurring when Mdm2 activity levels are low, promotes p53 nuclear export and the generation of a cytoplasmic p53 pools (27-32). Once p53 localizes to the mitochondria, both directly activated and enabled pathways are utilized to induce apoptosis (18). p53 interacts with anti-apoptotic members of the Bcl family such as BclXl and Bcl2 at the outer mitochondrial membrane to release and allow the oligomerization of the pro-apoptotic factors Bak and Bax. These in turn promote the formation of pores in the mitochondrial membrane resulting in the release of cytochrome c and other apoptotic activators from the mitochondria (21,22,(33)(34)(35). Alternatively, p53 can interact directly with Bak, releasing Bak from its inhibitory interaction with Mcl1 and thereby directly activating Bak-induced apoptosis (23, 36). Recently, a role for cytoplasmic p53 in autophagy was described, providing further evidence that changes on subcellular localization of p53 have pro...

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“…Although several ubiquitin ligases such as Pirh2, COP1 and ARF-BP1 have been reported to regulate p53 levels, MDM2 has been demonstrated to be the most important E3 ubiquitin ligase of p53 (Michael and Oren, 2002). Promoting p53 for degradation is the major mechanism by which MDM2 inhibits p53 (Itahana et al, 2007;Clegg et al, 2008). The MDM2 gene is a bona fide target downstream of the p53 gene, therefore activation of p53 upregulates its own inhibitor.…”

Section: Introductionmentioning

confidence: 99%

MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation

Galli

Rossi

D’Alessandra

et al. 2010

Journal of Cell Science

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SummaryTight control of p63 protein levels must be achieved under differentiation or apoptotic conditions. Here, we describe a new regulatory pathway for the Np63 protein. We found that MDM2 binds Np63 in the nucleus promoting its translocation to the cytoplasm. The MDM2 nuclear localization signal is required for Np63 nuclear export and subsequent degradation, whereas the MDM2 ringfinger domain is dispensable. Once exported to the cytoplasm by MDM2, p63 is targeted for degradation by the Fbw7 E3-ubiquitin ligase. Efficient degradation of Np63 by Fbw7 (also known as FBXW7) requires GSK3 kinase activity. By deletion and point mutations analysis we have identified a phosphodegron located in the  and  tail of p63 that is required for degradation. Furthermore, we show that MDM2 or Fbw7 depletion inhibits degradation of endogenous Np63 in cells exposed to UV irradiation, adriamycin and upon keratinocyte differentiation. Our findings suggest that following DNA damage and cellular differentiation MDM2 and Fbw7 can cooperate to regulate the levels of the pro-proliferative Np63 protein.

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Unlocking the Mdm2-p53 loop: Ubiquitin is the key

Cited by 59 publications

References 43 publications

Mdm2-mediated ubiquitylation: p53 and beyond

Mdm2-mediated ubiquitylation: p53 and beyond

MSL2 Promotes Mdm2-independent Cytoplasmic Localization of p53

MDM2 and Fbw7 cooperate to induce p63 protein degradation following DNA damage and cell differentiation

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