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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）：生长因子独立性-1（Gfi-1）是一种锌指（ZF）转录抑制因子，作为一种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在淋巴细胞和骨髓细胞的发育中发挥重要作用。已经表明，Gfi-1通过结合靶基因中的特异性DNA元件来抑制转录。Gfi-1抑制转录的分子机制仍然知之甚少。我们已经观察到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类似，Gfi-1抑制Miz-1对p21 Cip启动子的激活。值得注意的是，Gfi-1还抑制了Miz-1介导的不含Gfi-1结合位点的p21 Cip启动子片段的激活。Gfi-1在髓系32 D细胞中的过表达抑制DNA损伤诱导的p21 Cip上调。此外，Gfi-1和c-Myc协同作用以抑制由Miz-1或TGF-2处理的p21 Cip的激活。我们假设Gfi-1通过Miz-1被募集到p21 Cip，从而抑制p21 Cip的转录，并且Gfi-1可能直接或通过Miz-1与c-Myc相互作用，导致p21 Cip的协同抑制。目前的拨款提案的具体目标是研究Gfi-1如何抑制Miz-1介导的p21 Cip激活，并研究Gfi-1与c-Myc合作抑制p21 Cip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。癌细胞在控制细胞生长和存活的基因中存在突变，这些突变导致癌细胞不受控制地扩张。在这项提案中，我们将研究一种名为Gfi-1的核蛋白如何调节细胞生长和存活。由于Gfi-1的不适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，并将对设计治疗癌症的新治疗策略产生影响。