Gfi-1 in the regulation of p21Cip

Gfi-1 对 p21Cip 的调节

基本信息

批准号：
7364781
负责人：
FAN DONG
金额：
$ 21.6万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：生长因子独立-1 (Gfi-1) 是一种锌指 (ZF) 转录抑制因子，作为显性癌蛋白发挥作用，并在淋巴瘤发生中与 c-Myc 和 Pim-1 协同作用。 Gfi-1 在淋巴和骨髓细胞的发育中发挥重要作用。研究表明，Gfi-1 通过与靶基因中的特定 DNA 元件结合来抑制转录。 Gfi-1 抑制转录的分子机制仍知之甚少。我们观察到 Gfi-1 与 POZ 结构域 ZF 转录因子 Miz-1 相互作用，Miz-1 最初被鉴定为介导 c-Myc 抑制活性的 c-Myc 相互作用蛋白。与 c-Myc 一样，Gfi-1 抑制 Miz-1 对 p21Cip 启动子的激活。值得注意的是，Gfi-1 还抑制 Miz-1 介导的不包含 Gfi-1 结合位点的 p21Cip 启动子片段的激活。骨髓 32D 细胞中 Gfi-1 的过度表达抑制了 DNA 损伤诱导的 p21Cip 上调。此外，Gfi-1 和 c-Myc 协同作用，通过 Miz-1 或 TGF2 处理抑制 p21Cip 的激活。我们假设 Gfi-1 通过 Miz-1 被招募到 p21Cip，从而抑制 p21Cip 转录，并且 Gfi-1 可能直接或通过 Miz-1 与 c-Myc 相互作用，导致 p21Cip 的协同抑制。当前拨款提案的具体目标是研究 Gfi-1 如何抑制 Miz-1 介导的 p21Cip 激活，并研究 Gfi-1 与 c-Myc 合作抑制 p21Cip 的分子机制。这项研究可能揭示 Gfi-1 调节基因表达的新机制，也可能揭示 Gfi-1 和 Myc 在淋巴瘤发生中的功能协作。癌细胞中控制细胞生长和存活的基因发生突变，这些突变导致癌细胞不受控制地扩张。在本提案中，我们将研究一种称为 Gfi-1 的核蛋白如何调节细胞生长和存活。由于 Gfi-1 的不当激活与淋巴瘤有关，因此拟议的研究将阐明 Gfi-1 在淋巴瘤发展中的作用，并且还将对设计治疗癌症的新治疗策略产生影响。