Multiple sites of in vivo phosphorylation in the MDM2 oncoprotein cluster within two important functional domains

Hay, Trevor; Meek, David W.

doi:10.1016/s0014-5793(00)01850-0

Cited by 55 publications

(44 citation statements)

References 34 publications

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“…Posttransational modi®cations of the acidic domain could be necessary for MDM2 and p53 degradation. Very recently, two clusters of phosphorylation sites have been localised in the p53 binding domain and the acidic region (Hay and Meek, 2000). Ten out of 13 serines of the acidic region are deleted in DAD, raising the possibility that phosphorylation of the acidic domain could regulate p53 stability.…”

Section: Discussionmentioning

confidence: 99%

The contribution of the acidic domain of MDM2 to p53 and MDM2 stability

2001

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p53 and MDM2 are both degraded by the ubiquitinproteasome pathway. MDM2 binds p53 and promotes its rapid degradation. MDM2 is an E3 ligase that activates self and p53 ubiquitylation. Moreover, MDM2 nuclearcytoplasmic shuttling contributes to p53 degradation in the cytoplasm. We have identi®ed a new region of MDM2 which regulates the stability of both p53 and MDM2. The ®rst 50 amino-acids of the MDM2 acidic domain (222 ± 272) contribute to MDM2 and MDM2-mediated p53 degradation by a mechanism which is independent of either MDM2 E3-ligase activity or MDM2 nucleo-cytoplasmic shuttling. The transcriptional coactivator p300 could have been involved, since it binds to the MDM2 acidic domain. However, we found that p300 stabilises MDM2, even in absence of an intact acidic domain, indicating that the MDM2 acidic region contributes to proteolysis independently of p300. We propose that the MDM2 acidic domain is required for unbiquitylated MDM2 and p53 to be degraded by cytoplasmic proteasomes. Oncogene (2001) 20, 1267 ± 1275.

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Section: Discussionmentioning

confidence: 99%

The contribution of the acidic domain of MDM2 to p53 and MDM2 stability

2001

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“…Many of the same kinases also phosphorylate MDM2 in vitro, (Guerra et al, 1997;Mayo et al, 1997;Gotz et al, 1999;Khosravi et al, 1999) and MDM2 is heavily phosphorylated in vivo (Hay and Meek, 2000). Phosphorylation of MDM2 within the p53 binding domain, around the NLS, NES and in the acidic domain strongly suggests a regulatory role for these modifications (Hay and Meek, 2000;Maya and Oren, 2000).…”

Section: Phosphorylationmentioning

confidence: 99%

Activation and activities of the p53 tumour suppressor protein

Bálint¹,

Vousden²

2001

Br J Cancer

275

178

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The p53 tumour suppressor protein inhibits malignant progression by mediating cell cycle arrest, apoptosis or repair following cellular stress. One of the major regulators of p53 function is the MDM2 protein, and multiple forms of cellular stress activate p53 by inhibiting the MDM2-mediated degradation of p53. Mutations in p53, or disruption of the pathways that allow activation of p53, seem to be a general feature of all cancers. Here we review recent advances in our understanding of the pathways that regulate p53 and the pathways that are induced by p53, as well as their implications for cancer therapy. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…Although DNA damage is known to activate ATM kinase-induced phosphorylation of p53, it also targets Mdm2 at ser395 for phosphorylation in vitro (Maya et al, 2001). Furthermore, two multisite phosphorylation clusters were identified in vivo at the N-terminus of Mdm2, the region comprising the p53-binding domain and nuclear localization signal (Hay and Meek, 2000). Hypophosphorylation of putative sites within the acidic domain of Mdm2 reduced or ablated the ability of Mdm2 to degrade p53 (Blattner et al, 2002).…”

Section: Introductionmentioning

confidence: 99%