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Role of cofactors in nuclear hormone receptor function.

辅因子在核激素受体功能中的作用。

基本信息

批准号：
8510378
负责人：
Martin L. Privalsky
金额：
$ 2万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-20 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510378
关键词：
Address Binding Biological Biological Process Boxing Cell Proliferation Complex Defect Disease Endocrine Endocrine System Diseases Estrogen Receptors Exhibits Gene Targeting Genetic Transcription Goals Homeostasis Hormones Human Individual Investigation Knowledge Lead Lesion Ligands Mediating Messenger RNA Modeling Molecular N-terminal Normal Cell Nuclear Hormone Receptors Nuclear Receptors Phosphorylation Phosphotransferases Physiology Process Property Protein Isoforms Proteins RNA Splicing Recruitment Activity Repression Reproduction Research Research Personnel Retinoids Role Series Signal Transduction Specificity Steroids Thyroid Hormone Receptor Thyroid Hormone Receptor beta 1 Thyroid Hormones Tissues Touch sensation Transcriptional Activation Variant adipocyte differentiation cofactor gene repression human NCOR1 protein improved neoplastic programs receptor receptor function research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): We (and others) have identified a series of corepressor and coactivator proteins that physically associate with nuclear receptors, recruit additional proteins, and help mediate transcriptional repression or activation. Many signals that impact on nuclear receptor function manifest their effects through changes in corepressor and coactivator recruitment or function. We propose to continue our research into how the actions of nuclear receptors are mediated through these coregulators. We will address specific aspects of 5 broad questions: Specific Aim 1. How can otherwise closely-related isoforms of the same nuclear receptor display very different transcriptional properties: elucidation of the divergent transcriptional properties of thyroid hormone receptors beta 1 and beta 2. Specific aim 2. How do newly recognized N-terminal receptor interaction domains (nRID) in SMRT and N- CoR contribute to the actions of these corepressors? Specific Aim 3. How are the composition and transcriptional regulatory properties of the corepressor complex regulated by phosphorylation? Specific Aim 4. How does alternative mRNA splicing of SMRT and N-CoR customize their molecular properties? Specific Aim 5. How does alternative mRNA splicing of SMRT and N-CoR contribute to their biological functions? These experiments seek both to enhance our understanding of how nuclear receptors operate in mediating normal physiology, and to improve our knowledge of how aberrations in coregulator function lead to disease. Relevance: The proposed studies will improve our knowledge of how important hormones function in healthy individuals. They also will reveal how disruptions to these functions can lead to disease, and may provide clues resulting in improved treatments.

描述（由申请人提供）：我们（和其他人）已经鉴定了一系列辅阻遏物和辅激活蛋白，它们与核受体物理结合，募集额外的蛋白质，并帮助介导转录抑制或激活。许多影响核受体功能的信号通过改变辅阻遏物和辅激活物的募集或功能来表现其作用。我们建议继续研究核受体的作用是如何通过这些辅助调节因子介导的。我们将讨论5个广泛问题的具体方面：具体目标1。同一核受体的密切相关的亚型如何表现出非常不同的转录特性：甲状腺激素受体β 1和β 2不同转录特性的阐明。具体目标2。SMRT和N-CoR中新识别的N-末端受体相互作用结构域（nRID）如何促进这些辅阻遏物的作用？具体目标3。辅阻遏复合物的组成和转录调控特性是如何被磷酸化调控的？具体目标4。SMRT和N-CoR的选择性mRNA剪接如何定制其分子特性？具体目标5. SMRT和N-CoR的选择性mRNA剪接如何促进其生物学功能？这些实验旨在增强我们对核受体如何介导正常生理学的理解，并提高我们对辅调节因子功能异常如何导致疾病的认识。相关性：拟议的研究将提高我们对激素在健康个体中的重要作用的认识。它们还将揭示这些功能的破坏如何导致疾病，并可能提供改善治疗的线索。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The p160 coactivator PAS-B motif stabilizes nuclear receptor binding and contributes to isoform-specific regulation by thyroid hormone receptors.

p160 共激活因子 PAS-B 基序可稳定核受体结合，并有助于甲状腺激素受体的亚型特异性调节。

DOI：
10.1074/jbc.m109.007542
发表时间：
2009
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Privalsky,MartinL;Lee,Sangho;Hahm,JohnnieB;Young,BrianaM;Fong,RebeccaNG;Chan,IvanH
通讯作者：
Chan,IvanH

Pituitary resistance to thyroid hormone syndrome is associated with T3 receptor mutants that selectively impair beta2 isoform function.

垂体对甲状腺激素综合征的抵抗与选择性损害 β2 亚型功能的 T3 受体突变体有关。