RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Pikkarainen, S  Kennedy, RA  Marshall, AK  Tham el, L  Lay, K  Kriz, TA  Handa, BS  Clerk, A  Sugden, PH 
Citation: Pikkarainen S, etal., J Biol Chem. 2009 Oct 2;284(40):27195-210. Epub 2009 Jul 28.
RGD ID: 2317364
Pubmed: PMID:19638633   (View Abstract at PubMed)
PMCID: PMC2785647   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M109.037887   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Mdm2Ratcellular response to hydrogen peroxide  IEP cardiac myocytesRGD 
Mdm2Ratnegative regulation of protein processing  IMP caspase-3RGD 

Objects Annotated

Genes (Rattus norvegicus)
Mdm2  (MDM2 proto-oncogene)


Additional Information