THYROID HORMONE RECEPTOR AND GENE EXPRESSION
甲状腺激素受体和基因表达
基本信息
- 批准号:2016303
- 负责人:
- 金额:$ 12.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1988
- 资助国家:美国
- 起止时间:1988-07-01 至 1998-11-30
- 项目状态:已结题
- 来源:
- 关键词:DNA binding protein chemical binding conformation dimer fungal genetics gel mobility shift assay gene mutation genetic regulatory element genetic transcription hormone analog hormone receptor hormone regulation /control mechanism molecular cloning mutant protein sequence protein structure function reporter genes retinoid binding proteins thyroid hormones tissue /cell culture transcription factor triiodothyronine
项目摘要
The long range goal of this research is to understand the molecular basis
by which the nuclear thyroid hormone receptor (TR) mediates changes in
specific gene transcription. TR binds to specific DNA sequences (thyroid
hormone response elements or TREs) in both the absence and presence of
hormone. Upon binding of hormone, TR undergoes a conformational change
that converts it to a transcriptionally active state. The region of TR
between the DNA-binding domain and the C-terminal end (residues 170 to 456
of the beta form) is responsible for ligand binding, dimerization and
transcriptional activation. Little is currently known regarding these
important processes. The focus of this proposal is to identify the
critical amino acid residues responsible for these functions and to
understand the mechanism of ligand-mediated transcriptional activation by
TR. To accomplish these goals, we have established a yeast system in which
expression of the reporter gene, beta-galactosidase, is under control of
TR. Like many other mammalian transcription factors, TR can function in
yeast to activate transcription provided an appropriate DNA recognition
site is present. Using the yeast expression system, we have selected for
mutations of the C-terminal region of TR that are defective in promoting
transcriptional activation. These mutations fall into two general
categories: those that fail to bind hormone and those that bind hormone
normally, but cannot trans-activate. To evaluate the nature of these
functional domains, we will further characterize the mutations leading to
defects in hormone-binding and trans-activation. To identify amino acid
residues that are in close contact with hormone, we will screen for
mutations that alter the ligand-binding specificity of TR (Specific Aim
#1). Mutations that bind hormone, but are defective in trans-activation,
will be studied to determine whether the defects result from the failure
of TR to undergo the ligand-mediated conformational change or lie directly
within the trans-activation domain itself (Specific Aim #2). Recently,
several laboratories have shown that TR binding and transcriptional
activation on certain TREs can be enhanced by heterodimerization with the
retinoid X receptor (RXR). We will use the mutations that we have isolated
to study the roles of each of the receptor partners in the heterodimer in
the activation process (Specific Aim #3). Finally, we will use phenotypic
screening in yeast to identify regions of TR that are critical to the
process of heterodimerization and to determine whether distinct
dimerization domains are involved in interacting with different types of
TREs (Specific Aim #4). These studies will allow a better understanding of
the process of ligand-mediated transcriptional activation by TR and
provide valuable tools for future work to further explore this process.
这项研究的长期目标是了解其分子基础
项目成果
期刊论文数量(0)
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HOWARD C TOWLE其他文献
HOWARD C TOWLE的其他文献
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{{ truncateString('HOWARD C TOWLE', 18)}}的其他基金
Nutrient Control of Gene Expression & Cell Signaling
基因表达的营养控制
- 批准号:
7060812 - 财政年份:2005
- 资助金额:
$ 12.74万 - 项目类别:
Nutrient Control of Gene Expression & Cell Signaling
基因表达的营养控制
- 批准号:
6940522 - 财政年份:2005
- 资助金额:
$ 12.74万 - 项目类别:
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Grant-in-Aid for Scientific Research (A)