Ref-1 regulates the transactivation and pro-apoptotic functions of p53 in vivo

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Abstract
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.