Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage

Abstract

Upon DNA damage, tumor suppressor p53 determines cell fate byrepairing DNA lesions to survive or by inducing apoptosis to eliminatedamaged cells. The decision is based on its posttranslational modifications. Especially, p53 phosphorylation at Ser46 exerts apoptoticcell death. However, little is known about the precise mechanism ofp53 phosphorylation on the induction of apoptosis. Here, we showthat amphiregulin (AREG) is identified for a direct target of Ser46phosphorylation via the comprehensive expression analyses. Ser46-phosphorylated p53 selectively binds to the promoter region of AREGgene, indicating that the p53 modification changes target genes byaltering its binding affinity to the promoter. Although AREG belongsto a family of the epidermal growth factor, it also emerges in thenucleus under DNA damage. To clarify nuclear function of AREG, weanalyze AREG-binding proteins by mass spectrometry. AREG interactswith DEAD-box RNA helicase p68 (DDX5). Intriguingly, AREG regulates precursor microRNA processing (i.e., miR-15a) with DDX5 to reduce the expression of antiapoptotic protein Bcl-2. These findingscollectively support a mechanism in which the induction of AREGby Ser46-phosphorylated p53 is required for the microRNA biogenesisin the apoptotic response to DNA damage.