Gfi-1 in the regulation of p21Cip

Dong, Fan

Abstract

Growth factor independence-1 (Gfi-1) is a zinc-finger (ZF) transcriptional repressor that functions as a dominant oncoprotein and cooperates with c-Myc and Pim-1 in lymphomagenesis. Gfi-1 plays an important role in the development of lymphoid and myeloid cells. It has been shown that Gfi-1 represses transcription by binding to specific DNA elements in the target genes. The molecular mechanism by which Gfi-1 represses transcription is still poorly understood. We have observed that Gfi-1 interacts with the POZ domain ZF transcription factor Miz-1, originally identified as a c-Myc interacting protein that mediates c- Myc repression activity. Like c-Myc, Gfi-1 represses activation of the p21Cip promoter by Miz-1. Notably, Gfi-1 also repressed Miz-1-mediated activation of a p21Cip promoter fragment that contains no Gfi-1 binding site. Overexpression of Gfi-1 in myeloid 32D cells inhibited upregulation of p21Cip induced by DNA damage. Furthermore, Gfi-1 and c-Myc acted in collaboration to repress activation of p21Cip by Miz-1 or TGF2 treatment. We hypothesize that Gfi-1 is recruited to p21Cip via Miz-1, thereby repressing p21Cip transcription, and that Gfi-1 may interact with c-Myc, either directly or through Miz-1, resulting in synergistic repression of p21Cip.
The specific aims of the current grant proposal are to examine how Gfi-1 represses Miz-1-mediated activation of p21Cip and to investigate the molecular mechanism by which Gfi-1 collaborates with c-Myc in repressing p21Cip. The proposed research may reveal a novel mechanism by which Gfi-1 regulates gene expression and may also shed light on the functional collaboration between Gfi-1 and Myc in lymphomagenesis. Cancer cells have mutations in the genes that control cell growth and survival, and these mutations lead to uncontrolled expansion of cancer cells. In this proposal, we will investigate how a nuclear protein, called Gfi-1, acts to regulate cell growth and survival. Because inappropriate activation of Gfi-1 has been implicated in lymphoma, the proposed research will shed light on the role of Gfi-1 in lymphoma development and will also have implications for designing new therapeutic strategies for the treatment of cancer. ? ? ?