REGULATION OF GLUCOCORTICOID RECEPTOR BY PHOSPHORYLATION
通过磷酸化调节糖皮质激素受体
基本信息
- 批准号:2736871
- 负责人:
- 金额:$ 29.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-03-01 至 2003-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The overall objectives of this proposal are to characterize the
molecular mechanisms by which phosphorylation regulates
glucocorticoid receptor (GR) activity. GR is a hormone-dependent
transcription factor expressed in virtually all tissues, yet it
displays a remarkable capacity to regulate genes in a cell type-
specific manner. Although glucocorticoids act as the primary
signal in activating GR's transcriptional regulatory functions,
GR-mediated transcriptional activity is also regulated by
phosphorylation. The amino terminus of GR contains a
transcriptional activation domain that is phosphorylated at four
major sites in cultured mammalian cells. Several kinases have
been identified that phosphorylate GR in vitro at the identified
sites. Of these, the cyclin-dependent kinases (Cdks)
phosphorylate serine 232 (S232) and serine (S224), while c-Jun N-
terminal kinase (JNK) phosphorylates serine 246 (S246) and
glycogen synthase kinase-3 (GSK3) phosphorylates threonine 171
(T171). Phosphorylation of these sites is important for GR
function: serine to alanine mutations of S224 and S232 decrease
GR transcriptional activation, whereas alanine mutations of T171
and S246 increase GR transcriptional activation. Thus, GR-
mediated transcriptional activity is regulated both positively
and negatively by phosphorylation. We propose that
phosphorylation by multiple protein kinases enables GR to respond
to diverse extracellular signals. This ability to integrate
multiple signals in the form of phosphorylation permits a
flexibility in GR action that, in conjunction with the steroid
ligands, may be crucial in coordinating the cell type specific
actions of GR. We further hypothesize that phosphorylation
regulates GR's interaction with proteins involved in
transcriptional regulation. This hypothesis will be addressed by
expressing activators or inhibitors of Cdk, JNK and GSK3 in
cultured mammalian cells in transient transfection assays
designed to monitor GR-dependent transcriptional regulation. In
addition, we will identify and characterize proteins that
interact with the GR N-terminal transcriptional activation domain
in a phosphorylation-dependent manner using a protein interaction
screen in yeast. Gaining a mechanistic understanding of the
communication between multiple signaling pathways, as realized
through GR and its regulatory kinases, is fundamental to
understanding the mechanism of GR-regulated gene expression and
may reveal likely points of intervention to be exploited in the
development of new therapies for glucocorticoid-resistant
malignancies, such as breast cancer and acute lymphoblastic
leukemia.
本提案的总体目标是,
磷酸化调控的分子机制
糖皮质激素受体(GR)活性。 GR是一种依赖于
转录因子几乎在所有组织中表达,但它
显示出调节细胞基因的非凡能力
具体方式。 虽然糖皮质激素是主要的
激活GR转录调节功能的信号,
GR介导的转录活性也受
磷酸化 GR的氨基末端含有
转录激活结构域是磷酸化的四个
在培养的哺乳动物细胞中的主要位点。 有几种激酶
已经确定,在体外磷酸化糖皮质激素受体在确定的
网站. 其中,细胞周期蛋白依赖性激酶(Cdks)
磷酸化丝氨酸232(S232)和丝氨酸(S224),而c-Jun N-
末端激酶(JNK)磷酸化丝氨酸246(S246),
糖原合成酶激酶-3(GSK 3)磷酸化苏氨酸171
(T171)。 这些位点的磷酸化对于GR
功能:S224和S232的丝氨酸至丙氨酸突变减少
GR转录激活,而T171的丙氨酸突变
和S246增加GR转录激活。 因此,GR-
介导的转录活性受到正向调节,
而磷酸化则呈阴性。 我们建议
多种蛋白激酶的磷酸化使GR能够响应
多种细胞外信号。 这种整合能力
磷酸化形式的多种信号允许
GR作用的灵活性,与类固醇结合,
配体,可能是至关重要的协调细胞类型特异性
我们进一步假设,磷酸化
调节GR与蛋白质的相互作用,
转录调控 这一假设将通过以下方式加以解决:
表达Cdk、JNK和GSK 3的激活剂或抑制剂,
在瞬时转染测定中培养的哺乳动物细胞
用于监测GR依赖的转录调节。 在
此外,我们将鉴定和表征蛋白质,
与GR N-末端转录激活结构域相互作用
以磷酸化依赖的方式使用蛋白质相互作用
在酵母中筛选。 获得机械的理解
多个信号通路之间的通信,如所实现的
通过GR及其调节激酶,是至关重要的,
了解GR调节基因表达的机制,
可能揭示可能的干预点,
糖皮质激素抵抗的新疗法的开发
恶性肿瘤,如乳腺癌和急性淋巴细胞癌
白血病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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Michael J. Garabedian其他文献
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10.1016/j.celrep.2025.115527 - 发表时间:
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Matthew S. Rodeheffer
Brain-Derived Neurotrophic Factor Signaling Rewrites the Glucocorticoid Transcriptome via Glucocorticoid Receptor Phosphorylation
脑源性神经营养因子信号传导通过糖皮质激素受体磷酸化重写糖皮质激素转录组
- DOI:
10.1128/mcb.01139-13 - 发表时间:
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Freddy D. Jeanneteau
Sex differences in murine MASH induced by a fructose-palmitate-cholesterol-enriched diet
果糖 - 棕榈酸酯 - 胆固醇丰富饮食诱导的小鼠 MASH 中的性别差异
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10.1016/j.jhepr.2024.101222 - 发表时间:
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Ann Marie Schmidt
High dose methylprednisolone mediates YAP/TAZ-TEAD in vocal fold fibroblasts with macrophages
- DOI:
10.1038/s41598-025-95459-z - 发表时间:
2025-03-31 - 期刊:
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Ryosuke Nakamura;Renjie Bing;Gary J. Gartling;Michael J. Garabedian;Ryan C. Branski - 通讯作者:
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Modular Structure of Glucocorticoid Receptor Domains Is Not Equivalent to Functional Independence: STABILITY AND ACTIVITY OF THE STEROID BINDING DOMAIN ARE CONTROLLED BY SEQUENCES IN SEPARATE DOMAINS
- DOI:
10.1074/jbc.271.35.21430 - 发表时间:
1996-08-30 - 期刊:
- 影响因子:
- 作者:
Min Xu;Pradip K. Chakraborti;Michael J. Garabedian;Keith R. Yamamoto;S. Stoney Simons - 通讯作者:
S. Stoney Simons
Michael J. Garabedian的其他文献
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{{ truncateString('Michael J. Garabedian', 18)}}的其他基金
“Protection from MRSA lethality by inhibiting LXRα phosphorylation”
– 通过抑制 LXRα 磷酸化来防止 MRSA 致死 –
- 批准号:
10681027 - 财政年份:2023
- 资助金额:
$ 29.91万 - 项目类别:
Peptoid conjugates as inhibitors of androgen receptor dimerization and function in enzalutamide-resistant prostate cancer
类肽缀合物作为雄激素受体二聚化抑制剂及其在恩杂鲁胺耐药性前列腺癌中的功能
- 批准号:
9815670 - 财政年份:2019
- 资助金额:
$ 29.91万 - 项目类别:
Glucocorticoid receptor phosphorylation in endocrine adaptation to stress
糖皮质激素受体磷酸化在内分泌适应应激中的作用
- 批准号:
9883840 - 财政年份:2019
- 资助金额:
$ 29.91万 - 项目类别:
Targeting the glucocorticoid receptor in enzalutamide resistant prostate cancer
靶向恩杂鲁胺耐药性前列腺癌中的糖皮质激素受体
- 批准号:
9178221 - 财政年份:2016
- 资助金额:
$ 29.91万 - 项目类别:
REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE
前列腺雄激素受体活性的调节
- 批准号:
6381890 - 财政年份:2000
- 资助金额:
$ 29.91万 - 项目类别:
REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE
前列腺雄激素受体活性的调节
- 批准号:
6608814 - 财政年份:2000
- 资助金额:
$ 29.91万 - 项目类别:
REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE
前列腺雄激素受体活性的调节
- 批准号:
6524272 - 财政年份:2000
- 资助金额:
$ 29.91万 - 项目类别:
REGULATION OF ANDROGEN RECEPTOR ACTIVITY IN THE PROSTATE
前列腺雄激素受体活性的调节
- 批准号:
6153870 - 财政年份:2000
- 资助金额:
$ 29.91万 - 项目类别:
REGULATION OF GLUCOCORTICOID RECEPTOR BY PHOSPHORYLATION
通过磷酸化调节糖皮质激素受体
- 批准号:
6350717 - 财政年份:1999
- 资助金额:
$ 29.91万 - 项目类别:
REGULATION OF GLUCOCORTICOID RECEPTOR BY PHOSPHORYLATION
通过磷酸化调节糖皮质激素受体
- 批准号:
6150653 - 财政年份:1999
- 资助金额:
$ 29.91万 - 项目类别:
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