Cyclin-dependent kinase 6 associates with the androgen receptor and enhances its transcriptional activity in prostate cancer cells.
Cyclin-dependent kinase 6 (CDK6) binds to and is activated by cyclin D1 and thereby enhances the transition of cells through the G1 phase of the cell cycle. The present study indicates that, in human prostate cancer cells, CDK6 can also bind to the androgen receptor (AR) and stimulate its transcriptional activity in the presence of dihydrotestosterone. This effect of CDK6 does not require its kinase activity and is inhibited by cyclin D1 and p16INK4a. The T877A mutant of the AR frequently found in advanced cases of prostate cancer displays an exaggerated stimulation of transcriptional activity by CDK6. Androgen-sensitive LNCaP prostate cancer cells engineered to stably overexpress CDK6 display increased expression of the prostate-specific antigen and enhanced growth in the presence of dihydrotestosterone. CDK6 is present in the chromatin structure of these cells in association with the AR and the promoter region of the prostate-specific antigen gene. These findings suggest that CDK6 may play an important role in the development and/or progression of a subset of human prostate cancers by stimulating the activity of the AR.
Lim
Jin T E
JT
Department of Environmental Health Sciences, The Joseph L. Mailman School of Public Health, Columbia University, New York, NY 10027, USA.
Mansukhani
Mahesh
M
Weinstein
I Bernard
IB
D001483:Base Sequence; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008297:Male; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D018911:Trinucleotide Repeats
D004273:DNA, Neoplasm; D011944:Receptors, Androgen; D019938:Cyclin D1; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases