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The tumor suppressor p53 is a transcription factor that controls the mRNA level of downstream target genes involved in the regulation of the cell cycle (e.g., p21, Gadd45) and apoptosis (e.g., Puma, Bax), thus leading to tumor suppression. p53 activity is mainly regulated by its main E3 ubiquitin ligase, MDM2, and inhibition of MDM2 leads to p53 activation and tumor suppression.A small molecule MDM2 inhibitor, Nutlin-3a which binds to the p53-binding pocket in MDM2 to activate p53, is presently in cancer clinical trials. However, it is largely unknown which factors play crucial roles in p53-mediated tumor suppression. Toward this goal, we performed an unbiased screening by treating cells, that were infected with a human whole-genome lentiviral shRNA library, with Nutlin-3a. This screen identified several surviving colonies that contained a shRNA for Apobec4. Apobec4 is a member of the APOBEC family of RNA/DNA editing cytidine deaminases but lacks the cytidine deaminase and mutagenic activity. Hence, little is known about its biological function. Here, we demonstrated that cells downregulated for Apobec4 attenuated p53-mediated cell cycle arrest and apoptosis. As a mechanism, Apobec4 bound to p53 and enhanced p53’s binding to the p53-responsive elements in the promoter regions of the p53 target genes. Additionally, we found that Apobec4 mRNA expression was upregulated by p53. Our study, for the first time, reveals that Apobec4, a new binding partner of p53, is crucial for the proper function of p53 and in turn is a novel transcriptional target of p53, thus forming a positive feed-forward loop.

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APOBEC4, A Novel Regulator Of Cellular Aging, Cell Death, And Tumorigenesis



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