2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.

          Related collections

          Most cited references116

          • Record: found
          • Abstract: found
          • Article: not found

          Mdm2 promotes the rapid degradation of p53.

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.

            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.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.

              The tumor suppressor p53 is degraded by the ubiquitin-proteasome system. p53 was polyubiquitinated in the presence of E1, UbcH5 as E2 and MDM2 oncoprotein. A ubiquitin molecule bound MDM2 through sulfhydroxy bond which is characteristic of ubiquitin ligase (E3)-ubiquitin binding. The cysteine residue in the carboxyl terminus of MDM2 was essential for the activity. These data suggest that the MDM2 protein, which is induced by p53, functions as a ubiquitin ligase, E3, in human papillomavirus-uninfected cells which do not have E6 protein.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                05 August 2020
                2020
                : 10
                : 1389
                Affiliations
                [1] 1College of Pharmaceutical Sciences, Zhejiang Chinese Medical University , Hangzhou, China
                [2] 2Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Zhejiang Cancer Hospital , Hangzhou, China
                [3] 3First Clinical Medical College, Zhejiang Chinese Medical University , Hangzhou, China
                Author notes

                Edited by: David A. Gewirtz, Virginia Commonwealth University, United States

                Reviewed by: Aart Jochemsen, Leiden University Medical Center, Netherlands; Fabiola Moretti, Italian National Research Council, Italy

                *Correspondence: Jiang-Jiang Qin jqin@ 123456zcmu.edu.cn ; zylysjtu@ 123456hotmail.com

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.01389
                7419686
                32850448
                58209009-f6ef-4d30-9416-f8a811cd73c2
                Copyright © 2020 Yu, Xu, Mo, Yuan, Cheng and Qin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 April 2020
                : 01 July 2020
                Page count
                Figures: 3, Tables: 2, Equations: 0, References: 136, Pages: 14, Words: 10939
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                mdmx,mdm2,p53,oncogene,tumor suppressor,inhibitors
                Oncology & Radiotherapy
                mdmx, mdm2, p53, oncogene, tumor suppressor, inhibitors

                Comments

                Comment on this article