P53 inhibits the upregulation of sirtuin 1 expression induced by c-Myc

Abstract

Sirtuin 1 (Sirt1), a conserved NAD+ dependent deacetylase, is a mediator of life span by calorie restriction. However, Sirt1 may paradoxically increase the risk of cancer. Accordingly, the expression level of Sirt1 is selectively elevated in numerous types of cancer cell; however, the mechanisms underlying the differential regulation remain largely unknown. The present study demonstrated that oncoprotein c-Myc was a direct regulator of Sirt1, which accounts for the upregulation of Sirt1 expression only in the cells without functional p53. In p53 deficient cells, the overexpression of c-Myc increased Sirt1 mRNA and protein expression levels as well as its promoter activity, whereas the inhibitor of c-Myc, 10058-F4, induced decreased Sirt1 basal mRNA and protein expression levels. Deletion/mutation mapping analyses revealed that c-Myc bound to the conserved E-box[-189 to -183 base pair (bp)] of the Sirt1 promoter. In addition, p53 and c-Myc shared at least response element and the presence of p53 may block the binding of c-Myc to the Sirt1 promoter, thus inhibit the c-Myc mediated upregulation of Sirt1 promoter activity. The present study indicated that the expression level of Sirt1 was tightly regulated by oncoprotein c-Myc and tumor suppressor p53, which aids an improved understanding of its expression regulation and tumor promoter role in certain conditions.