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.
Highlights
Growth Factor Independence 1 (GFI1) encodes a nuclear zinc-finger (ZF) transcriptional repressor that plays a critical role in hematopoiesis [1,2]
To investigate the mechanism whereby Gfi1 inhibited DNA damage-induced apoptosis, we examined the expression of Bax, Bak and Bcl-2 in Ba/F3 and Ramos cells transduced with the Doxy-responsive Gfi1 expression construct as well as in the GFI1 knocked down HL-60 and U937 cells
We have demonstrated that GFI1 transcription is repressed by p53 in hematopoietic cells
Summary
Growth Factor Independence 1 (GFI1) encodes a nuclear zinc-finger (ZF) transcriptional repressor that plays a critical role in hematopoiesis [1,2]. Loss of Gfi in mice leads to markedly reduced thymic cellularity due to increased apoptosis and reduced proliferation during early T cell development. The tumor suppressor p53 is a transcription factor that is activated by cellular stresses such as DNA damage and oncogene stimulation [22,23]. In addition to transcriptional activation, p53 functions to repress certain genes and recent studies indicate that transcriptional repression by p53 is required for its tumor suppressor activity [25,26]. It is still poorly understood about the molecular mechanisms by which p53 represses gene expression. Our data identify GFI1 as a new p53-repressed target gene and suggest that GFI1 downregulation may be important for the tumor suppressor action of p53 in the hematopoietic system
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