NDLI: Regulation of Expression of the Rat Orthologue of Mouse Double Minute 2 (MDM2) by $H_{2}O_{2}-induced$ Oxidative Stress in Neonatal Rat Cardiac Myocytes

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Regulation of Expression of the Rat Orthologue of Mouse Double Minute 2 (MDM2) by $H_{2}O_{2}-induced$ Oxidative Stress in Neonatal Rat Cardiac Myocytes

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Regulation of Expression of the Rat Orthologue of Mouse Double Minute 2 (MDM2) by $H_{2}O_{2}-induced$ Oxidative Stress in Neonatal Rat Cardiac Myocytes

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Kriz, Thomas A. Clerk, Angela Lay, Kenneth Marshall, Andrew K. Handa, Balvinder S. Kennedy, Robert A. Sugden, Peter H. Pikkarainen, Sampsa Tham, El Li
Description	Author Affiliation: Pikkarainen S ( National Heart and Lung Institute Division, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.)
Abstract	The Mdm2 ubiquitin ligase is an important regulator of p53 abundance and p53-dependent apoptosis. Mdm2 expression is frequently regulated by a p53 Mdm2 autoregulatory loop whereby p53 stimulates Mdm2 expression and hence its own degradation. Although extensively studied in cell lines, relatively little is known about Mdm2 expression in heart where oxidative stress (exacerbated during ischemia-reperfusion) is an important pro-apoptotic stimulus. We demonstrate that Mdm2 transcript and protein expression are induced by oxidative stress (0.2 mm H(2)O(2)) in neonatal rat cardiac myocytes. In other cells, constitutive Mdm2 expression is regulated by the P1 promoter (5' to exon 1), with inducible expression regulated by the P2 promoter (in intron 1). In myocytes, H(2)O(2) increased Mdm2 expression from the P2 promoter, which contains two p53-response elements (REs), one AP-1 RE, and two Ets REs. H(2)O(2) did not detectably increase expression of p53 mRNA or protein but did increase expression of several AP-1 transcription factors. H(2)O(2) increased binding of AP-1 proteins (c-Jun, JunB, JunD, c-Fos, FosB, and Fra-1) to an Mdm2 AP-1 oligodeoxynucleotide probe, and chromatin immunoprecipitation assays showed it increased binding of c-Jun or JunB to the P2 AP-1 RE. Finally, antisense oligonucleotide-mediated reduction of H(2)O(2)-induced Mdm2 expression increased caspase 3 activation. Thus, increased Mdm2 expression is associated with transactivation at the P2 AP-1 RE (rather than the p53 or Ets REs), and Mdm2 induction potentially represents a cardioprotective response to oxidative stress.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	40
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2009-10-02
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Gene Expression Regulation Drug Effects Hydrogen Peroxide Pharmacology Myocytes, Cardiac Oxidative Stress Proto-Oncogene Proteins C-mdm2 Genetics Metabolism Sequence Homology, Amino Acid Animals Animals, Newborn Apoptosis Caspase 3 Introns Mice Molecular Sequence Data Cytology Promoter Regions, Genetic RNA, Messenger Response Elements Transcription Factor AP-1 Transcriptional Activation Up-Regulation Research Support, Non-U.S. Gov't Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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