Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation: Clinical implications for the nervous system response to glucocorticoids and stress

Tomoshige Kino, Takamasa Ichijo, Niranjana D. Amin, Sashi Kesavapany, Yonghong Wang, Nancy Kim, Sandesh Rao, Audrey Player, Ya Li Zheng, Michael J. Garabedian, Ernest Kawasaki, Harish C. Pant, George P. Chrousos

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Glucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system and influence diverse functions of neuronal cells. We found that cyclin-dependent kinase 5 (CDK5), which plays important roles in the morphogenesis and functions of the nervous system and whose aberrant activation is associated with development of neurodegenerative disorders, interacted with the ligand-binding domain of the glucocorticoid receptor (GR) through its activator p35 or its active proteolytic fragment p25. CDK5 phosphorylated GR at multiple serines, including Ser203 and Ser211 of its N-terminal domain, and suppressed the transcriptional activity of this receptor on glucocorticoid-responsive promoters by attenuating attraction of transcriptional cofactors to DNA. In microarray analyses using rat cortical neuronal cells, the CDK5 inhibitor roscovitine differentially regulated the transcriptional activity of the GR on more than 90% of the endogenous glucocorticoid-responsive genes tested. Thus, CDK5 exerts some of its biological activities in neuronal cells through the GR, dynamically modulating GR transcriptional activity in a target promoter-dependent fashion.

Original languageEnglish
Pages (from-to)1552-1568
Number of pages17
JournalMolecular Endocrinology
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 2007
Externally publishedYes

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Cyclin-Dependent Kinase 5
Glucocorticoid Receptors
Nervous System
Glucocorticoids
Phosphorylation
Microarray Analysis
Morphogenesis
Neurodegenerative Diseases
Serine
Homeostasis
Central Nervous System
Ligands
DNA
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation : Clinical implications for the nervous system response to glucocorticoids and stress. / Kino, Tomoshige; Ichijo, Takamasa; Amin, Niranjana D.; Kesavapany, Sashi; Wang, Yonghong; Kim, Nancy; Rao, Sandesh; Player, Audrey; Zheng, Ya Li; Garabedian, Michael J.; Kawasaki, Ernest; Pant, Harish C.; Chrousos, George P.

In: Molecular Endocrinology, Vol. 21, No. 7, 07.2007, p. 1552-1568.

Research output: Contribution to journalArticle

Kino, Tomoshige ; Ichijo, Takamasa ; Amin, Niranjana D. ; Kesavapany, Sashi ; Wang, Yonghong ; Kim, Nancy ; Rao, Sandesh ; Player, Audrey ; Zheng, Ya Li ; Garabedian, Michael J. ; Kawasaki, Ernest ; Pant, Harish C. ; Chrousos, George P. / Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylation : Clinical implications for the nervous system response to glucocorticoids and stress. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 7. pp. 1552-1568.
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