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 G1phase 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 transcripti...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 14; pp. 5156 - 5161
Main Authors Jin T. E. Lim, Mansukhani, Mahesh, Weinstein, I. Bernard, Lieberman, Seymour
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 05.04.2005
National Acad Sciences
Subjects
Androgens
Antibodies
Base Sequence
Biological Sciences
Cell cycle
Cell growth
Cell Line, Tumor
Cells
Cyclin D1 - metabolism
Cyclin-Dependent Kinase 6
Cyclin-dependent kinases
Cyclin-Dependent Kinases - genetics
Cyclin-Dependent Kinases - metabolism
Cyclins
Directional control
DNA, Neoplasm - genetics
Gene Expression
Genes
Humans
Male
Plasmids
Point Mutation
Promoter regions
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Signal Transduction
Transcription, Genetic
Transfection
Trinucleotide Repeats
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Summary:Cyclin-dependent kinase 6 (CDK6) binds to and is activated by cyclin D1 and thereby enhances the transition of cells through the G1phase 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 p16INK4 a. 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.
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Author contributions: J.T.E.L. and I.B.W. designed research; J.T.E.L. and M.M. performed research; J.T.E.L., M.M., and I.B.W. analyzed data; and J.T.E.L. and I.B.W. wrote the paper.
Abbreviations: CDK, cyclin-dependent kinase; HA, hemagglutinin; PSA, prostate-specific antigen; DHT, dihydrotestosterone; AR, androgen receptor.
Communicated by Seymour Lieberman, St. Luke's–Roosevelt Institute for Health Sciences, New York, NY, February 16, 2005
To whom correspondence should be addressed. E-mail: ibw1@columbia.edu.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0501203102