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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

Reproductive Biology and Medicine Branch (T.K., T.I., N.K., S.R., G.P.C.), National Institute of Child Health and Human Development and Laboratory of Neurochemistry (N.D.A., S.K., Y.-L.Z., H.C.P.), National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892; Microarray Facility (Y.W., A.P., E.K.), Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland 20877; Department of Microbiology and Urology (M.J.G.), New York University Cancer Institute, New York University School of Medicine, New York, New York 10016; and First Department of Pediatrics (G.P.C.), Athens University Medical School, 11527 Athens, Greece

Address all correspondence and requests for reprints to: Tomoshige Kino, M.D., Ph.D., Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Clinical Research Center, Room 1-3140, 10 Center Drive MSC 1109, Bethesda, Maryland 20892-1109. E-mail: kinot{at}mail.nih.gov.

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.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   p300

Ligands:   Dexamethasone

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