Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo.
Ref-1 is a multifunctional protein that stimulates DNA binding by a number of transcription factors and serves as the abasic (A/P) endonuclease in base excision repair. Ref-1 was discovered to be a potent activator of p53 DNA binding in vitro. To address the physiological significance of the effects of Ref-1 on p53, we have analyzed its role in regulating p53 function in vivo. We found that Ref-1 over-expression enhances the ability of p53 to transactivate a number of p53 target promoters and increases the ability of p53 to stimulate endogenous p21 and cyclin G expression. Additionally, it was observed that Ref-1 associates with p53 in vivo and in vitro. Importantly, downregulation of Ref-1 (by antisense) causes a marked reduction in p53 induction of p21 mRNA and protein, as well as diminished ability of p53 to transactivate the p21 and Bax promoters. Moreover, Ref-1 levels are correlated with the extent of apoptosis induced by p53. Finally, we observed that Ref-1 cooperates with a DNA-damaging compound, camptothecin, to stimulate the transcriptional activity of p53. Together these data indicate that Ref-1 is a key cellular regulator of p53.
Gaiddon
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Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
Moorthy
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NC
Prives
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D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D001483:Base Sequence; D002166:Camptothecin / Q000494:pharmacology; D019757:Carbon-Oxygen Lyases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D015536:Down-Regulation; D016158:Genes, p53; D006801:Humans; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D019757:Carbon-Oxygen Lyases; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D002166:Camptothecin