REGULATION OF GLUCOCORTICOID RECEPTOR BY PHOSPHORYLATION

通过磷酸化调节糖皮质激素受体

基本信息

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.
本建议的总体目标是描述

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

Dietary oleic acid drives obesogenic adipogenesis via modulation of LXRα signaling
膳食油酸通过调节 LXRα 信号通路驱动致肥胖性脂肪生成。
  • DOI:
    10.1016/j.celrep.2025.115527
  • 发表时间:
    2025-04-22
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Allison Wing;Elise Jeffery;Christopher D. Church;Jennifer Goodell;Rocío del M. Saavedra-Peña;Moumita Saha;Brandon Holtrup;Maud Voisin;N. Sima Alavi;Mariana Floody;Zenan Wang;Thomas E. Zapadka;Michael J. Garabedian;Rohan Varshney;Michael C. Rudolph;Matthew S. Rodeheffer
  • 通讯作者:
    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:
    2013
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    W. M. Lambert;Chong;Thomas A. Neubert;Moses V. Chao;Michael J. Garabedian;Freddy D. Jeanneteau;Thomas A. Neubert;Moses V. Chao;Michael J. Garabedian;Freddy D. Jeanneteau
  • 通讯作者:
    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
  • DOI:
    10.1016/j.jhepr.2024.101222
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
    7.500
  • 作者:
    Lakshmi Arivazhagan;Sofie Delbare;Robin A. Wilson;Michaele B. Manigrasso;Boyan Zhou;Henry H. Ruiz;Kaamashri Mangar;Ryoko Higa;Emily Brown;Huilin Li;Michael J. Garabedian;Ravichandran Ramasamy;Kathryn J. Moore;Edward A. Fisher;Neil D. Theise;Ann Marie Schmidt
  • 通讯作者:
    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:
  • 影响因子:
    3.900
  • 作者:
    Ryosuke Nakamura;Renjie Bing;Gary J. Gartling;Michael J. Garabedian;Ryan C. Branski
  • 通讯作者:
    Ryan C. Branski
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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酿酒酵母中细胞周期蛋白依赖性激酶 8 (Cdk8) 底物的鉴定和表征
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The essential role of cyclin-dependent kinase CRK9 in trypanosome pre-mRNA processing
细胞周期蛋白依赖性激酶 CRK9 在锥虫前 mRNA 加工中的重要作用
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细胞周期蛋白依赖性激酶 4/6 抑制剂耐药性激素受体阳性乳腺癌的脆弱性和治疗策略的发现和验证
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细胞周期蛋白依赖性激酶 4/6 (CDK4/6) 作为胶质母细胞瘤的治疗靶点
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Cyclin Dependent Kinase 4/6 (CDK4/6) as a Therapeutic Target in Glioblastoma
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  • 批准号:
    10376267
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    2020
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