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      The MDM2-p53 pathway revisited

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          Abstract

          The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.

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          Mdm2 promotes the rapid degradation of p53.

          Y Haupt, R Maya, A Kazaz … (1997)
          The p53 tumour-suppressor protein exerts antiproliferative effects, including growth arrest and apoptosis, in response to various types of stress. The activity of p53 is abrogated by mutations that occur frequently in tumours, as well as by several viral and cellular proteins. The Mdm2 oncoprotein is a potent inhibitor of p53. Mdm2 binds the transcriptional activation domain of p53 and blocks its ability to regulate target genes and to exert antiproliferative effects. On the other hand, p53 activates the expression of the mdm2 gene in an autoregulatory feedback loop. The interval between p53 activation and consequent Mdm2 accumulation defines a time window during which p53 exerts its effects. We now report that Mdm2 also promotes the rapid degradation of p53 under conditions in which p53 is otherwise stabilized. This effect of Mdm2 requires binding of p53; moreover, a small domain of p53, encompassing the Mdm2-binding site, confers Mdm2-dependent detstabilization upon heterologous proteins. Raised amounts of Mdm2 strongly repress mutant p53 accumulation in tumour-derived cells. During recovery from DNA damage, maximal Mdm2 induction coincides with rapid p53 loss. We propose that the Mdm2-promoted degradation of p53 provides a new mechanism to ensure effective termination of the p53 signal.
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            The first 30 years of p53: growing ever more complex.

            Arnold J. Levine, Moshe Oren (2009)
            Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess.
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              The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.

              Jamil Momand, Gerard P. Zambetti, David Olson … (1992)
              A cellular phosphoprotein with an apparent molecular mass of 90 kd (p90) that forms a complex with both mutant and wild-type p53 protein has been characterized, purified, and identified. The protein was identified as a product of the murine double minute 2 gene (mdm-2). The mdm-2 gene enhances the tumorigenic potential of cells when it is overexpressed and encodes a putative transcription factor. To determine if mdm-2 could modulate p53 transactivation, a p53-responsive element from the muscle creatine kinase gene was employed. A wild-type p53-expressing plasmid enhanced the expression of the p53-responsive element when cotransfected into cells that contain no endogenous p53. When a cosmid expressing mdm-2 was transfected with this p53-expressing plasmid, the transactivation of the p53-responsive element was inhibited. Thus, a product of the mdm-2 oncogene forms a tight complex with the p53 protein, and the mdm-2 oncogene can inhibit p53-mediated transactivation.
              Article 0 comments Cited 435 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biomed Res
                Journal ID (iso-abbrev): J Biomed Res
                Journal ID (publisher-id): JBR
                Title: Journal of Biomedical Research
                Publisher: Editorial Department of Journal of Biomedical Research
                ISSN (Print): 1674-8301
                Publication date (Print): July 2013
                Publication date (Electronic): 6 June 2013
                Volume: 27
                Issue: 4
                Pages: 254-271
                Affiliations
                [a ]Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA;
                [b ]Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA;
                [c ]Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
                Author notes
                [✉ ]Corresponding author: Dr. Ruiwen Zhang, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, TX 79106, USA. Tel: +1-8063564750 x230; Fax: +1-8063564034, E-mail: ruiwen.zhang@ 123456ttuhsc.edu .

                The authors reported no conflict of interests.

                Article
                Publisher ID: jbr-27-04-254
                DOI: 10.7555/JBR.27.20130030
                PMC ID: 3721034
                PubMed ID: 23885265
                SO-VID: 4e8353c3-bc48-4a0d-932c-98c42a571514
                Copyright © © 2013 by the Journal of Biomedical Research. All rights reserved.
                History
                Date received : 15 March 2013
                Date accepted : 12 April 2013
                Categories
                Subject: Invited Review

                Keywords: oncogene,tumor suppressor,mdm2-p53 interaction,cancer therapy
                Data availability:
                Keywords: oncogene, tumor suppressor, mdm2-p53 interaction, cancer therapy

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