Cyclin-dependent kinase 5 modulates the transcriptional activity of the mineralocorticoid receptor and regulates expression of brain-derived neurotrophic factor.
Glucocorticoids, major end effectors of the stress response, play an essential role in the homeostasis of the central nervous system (CNS) and contribute to memory consolidation and emotional control through their intracellular receptors, the glucocorticoid and mineralocorticoid receptors. Cyclin-dependent kinase 5 (CDK5), on the other hand, plays important roles in the morphogenesis and functions of the central nervous system, and its aberrant activation has been associated with development of neurodegenerative disorders. We previously reported that CDK5 phosphorylated the glucocorticoid receptor and modulated its transcriptional activity. Here we found that CDK5 also regulated mineralocorticoid receptor-induced transcriptional activity by phosphorylating multiple serine and threonine residues located in its N-terminal domain through physical interaction. Aldosterone and dexamethasone, respectively, increased and suppressed mRNA/protein expression of brain-derived neurotrophic factor (BDNF) in rat cortical neuronal cells, whereas the endogenous glucocorticoid corticosterone showed a biphasic effect. CDK5 enhanced the effect of aldosterone and dexamethasone on BDNF expression. Because this neurotrophic factor plays critical roles in neuronal viability, synaptic plasticity, consolidation of memory, and emotional changes, we suggest that aberrant activation of CDK5 might influence these functions through corticosteroid receptors/BDNF.
Kino
Tomoshige
T
Unit on Molecular Hormone Action, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1109, USA. kinot@mail.nih.gov
Jaffe
Howard
H
Amin
Niranjana D
ND
Chakrabarti
Mayukh
M
Zheng
Ya-Li
YL
Chrousos
George P
GP
Pant
Harish C
HC
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D010766:Phosphorylation / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D011687:Purines / Q000494:pharmacology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D000077546:Roscovitine; D020798:Two-Hybrid System Techniques
D019208:Brain-Derived Neurotrophic Factor; D011687:Purines; D018161:Receptors, Mineralocorticoid; D000077546:Roscovitine; D000450:Aldosterone; D003907:Dexamethasone; D051360:Cyclin-Dependent Kinase 5; D003345:Corticosterone