The regulation of MDM2 by multisite phosphorylation-Opportunities for molecular-based intervention to target tumours?

David W. Meek, Ted R. Hupp

    Research output: Contribution to journalReview articlepeer-review

    52 Citations (Scopus)

    Abstract

    The p53 tumour suppressor is a tightly controlled transcription factor that coordinates a broad programme of gene expression in response to various cellular stresses leading to the outcomes of growth arrest, senescence, or apoptosis. MDM2 is an E3 ubiquitin ligase that plays a key role in maintaining p53 at critical physiological levels by targeting it for proteasome-mediated degradation. Expression of the MDM2 gene is p53-dependent and thus p53 and MDM2 operate within a negative feedback loop in which p53 controls the levels of its own regulator. Induction and activation of p53 involves mainly the uncoupling of p53 from its negative regulators, principally MDM2 and MDMX, an MDM2-related and -interacting protein that inhibits p53 transactivation function. MDM2 is tightly regulated through various mechanisms including gene expression, protein turnover (mediated by auto-ubiquitylation), protein-protein interaction with key regulators, and post-translational modification, mainly, but not exclusively, by multisite phosphorylation. The purpose of the present article into review our current knowledge of the signalling mechanisms that focus on MDM2, and indeed MDMX, through both phosphorylation mechanisms and peptide-docking events and to consider the wider implications of these regulatory events in the context of coordinated regulation of the p53 response. This analysis also provides an opportunity to consider the signalling pathways regulating MDM2 as potential targets for non-genotoxic therapies aimed at restoring p53 function in tumour cells. (C) 2009 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)19-28
    Number of pages10
    JournalSeminars in Cancer Biology
    Volume20
    Issue number1
    DOIs
    Publication statusPublished - Feb 2010

    Keywords

    • MDM2
    • Phosphorylation
    • p53
    • MDMX
    • Anti-tumour
    • Peptide-docking
    • Therapeutics
    • PROTEIN-KINASE CK2
    • ATM-DEPENDENT PHOSPHORYLATION
    • P53 IN-VIVO
    • DNA-DAMAGE
    • ACIDIC DOMAIN
    • LIGASE ACTIVITY
    • ACTIVATES P53
    • MDM2-DEFICIENT MICE
    • EMBRYONIC LETHALITY
    • SUPPRESSOR PATHWAY

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