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.
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.
Kino
Tomoshige
T
Reproductive Biology and Medicine Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland 20892, USA. kinot@mail.nih.gov
Ichijo
Takamasa
T
Amin
Niranjana D
ND
Kesavapany
Sashi
S
Wang
Yonghong
Y
Kim
Nancy
N
Rao
Sandesh
S
Player
Audrey
A
Zheng
Ya-Li
YL
Garabedian
Michael J
MJ
Kawasaki
Ernest
E
Pant
Harish C
HC
Chrousos
George P
GP
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D051360:Cyclin-Dependent Kinase 5 / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011687:Purines / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000077546:Roscovitine; D012694:Serine / Q000737:chemistry; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D020798:Two-Hybrid System Techniques
D017931:DNA Primers; D008024:Ligands; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; C089495:neuronal Cdk5 activator (p25-p35); D000077546:Roscovitine; D012694:Serine; D003907:Dexamethasone; D051360:Cyclin-Dependent Kinase 5