Functional analysis of differentiation through PPARg

通过 PPARg 进行分化的功能分析

• 批准号: 6583521
• 负责人: WENLI YANG
• 金额: $ 4.16万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6583521
• 关键词: 3T3 cells; SDS polyacrylamide gel electrophoresis; adipocytes; affinity chromatography; autoradiography; cell differentiation; cofactor; electrospray ionization mass spectrometry; green fluorescent proteins; hormone receptor; hormone regulation /control mechanism; peroxisome proliferator activated receptor; phosphorylation; postdoctoral investigator; protein kinase; thermogenesis; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): PPARgamma is a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear hormone receptor (NHR) superfamily of ligand-dependent transcription factors. It plays an important role in a number of pathways including in adipose differentiation, glucose homeostasis, atherosclerosis, and cancer. PPARgamma has a dominant effect in induction of adipose differentiation upon ligand activation. A major portion of this adipogenic activity is regulated by the N-terminal region of PPARgamma, a domain whose function is poorly characterized in PPARgamma and in the nuclear receptor family in general. The N-terminal region is also phosphorylated in response to growth factor stimulation, which in turn modulates PPARgamma activity. The proposed research aims to define and characterize the role of this domain in the regulation of PPARgamma function. Since this region contains adipogenic activity lacking or reduced in other PPAR isoforms, this work will also be important in defining functional specificity between different nuclear receptors that bind to the same DNA sequences. An adipogenic cofactor PGC-2 binds to this region and enhances transcriptional and adipogenic activities of PPARgamma. The function of PGC-2 will be characterized in detail. Secondly, novel factors that bind specifically to the PPARgamma N-terminus that regulate its function will be identified using biochemical methods. In addition, factors that associate with the N-terminus in a phosphorylation-dependent manner will also be isolated.

描述（由申请人提供）：PPARγ是配体依赖性转录因子核激素受体（NHR）超家族的过氧化物酶体增殖物激活受体（PPAR）亚家族的成员。它在许多途径中发挥着重要作用，包括脂肪分化、葡萄糖稳态、动脉粥样硬化和癌症。 PPARgamma 在配体激活后诱导脂肪分化中具有主导作用。这种脂肪生成活性的主要部分是由 PPARgamma 的 N 末端区域调节的，该结构域的功能在 PPARgamma 和一般核受体家族中的特征很少。 N 末端区域也会因生长因子刺激而磷酸化，进而调节 PPARgamma 活性。本研究旨在定义和表征该结构域在 PPARgamma 功能调节中的作用。由于该区域含有其他 PPAR 同工型中缺乏或减少的脂肪生成活性，因此这项工作对于定义与相同 DNA 序列结合的不同核受体之间的功能特异性也很重要。脂肪形成辅助因子 PGC-2 与该区域结合并增强 PPARgamma 的转录和脂肪形成活性。 PGC-2的功能将被详细描述。其次，将使用生化方法鉴定特异性结合 PPARgamma N 末端并调节其功能的新因子。此外，还将分离出以磷酸化依赖性方式与 N 末端相关的因子。