GFI1 is repressed by p53 and inhibits DNA damage-induced apoptosis.

Abstract

GFI1 is a transcriptional repressor that plays a critical role in hematopoiesis and has also been implicated in lymphomagenesis. It is still poorly understood how GFI1 expression is regulated in the hematopoietic system. We show here that GFI1 transcription was repressed by the tumor suppressor p53 in hematopoietic cells. Knockdown of p53 resulted in increased GFI1 expression and abolished DNA damage-induced GFI1 downregulation. In contrast, GFI1 expression was reduced and its downregulation in response to DNA damage was rescued upon restoration of p53 function in p53-deficient cells. In luciferase reporter assays, wild type p53, but not a DNA binding-defective p53 mutant, repressed the GFI1 promoter. Chromatin immunoprecipitation (ChIP) assays demonstrated that p53 bound to the proximal region of the GFI1 promoter. Detailed mapping of the GFI1 promoter indicated that GFI1 core promoter region spanning from -33 to +6 bp is sufficient for p53-mediated repression. This core promoter region contains a putative p53 repressive response element, mutation of which abolished p53 binding to and repression of GFI1 promoter. Significantly, apoptosis induced by DNA damage was inhibited upon Gfi1 overexpression, but augmented following GFI1 knockdown. Our data establish for the first time that GFI1 is repressed by p53 and add to our understanding of the roles of GFI1 in normal hematopoiesis and lymphomagenesis.