D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability.
D-type cyclins regulate distinct cellular processes, such as mitotic cell cycle control, differentiation, and transcription. We have previously shown that the D-type cyclins are critical for the androgen-dependent proliferation of prostate cells. Here, we sought to determine whether cyclin D1 directly influences the transactivation potential of the androgen receptor, a transcription factor that strongly influences androgen-dependent proliferation. We found that ligand-mediated transcriptional activation of a physiological target, prostate-specific antigen, by the androgen receptor was inhibited by cyclins D1 and D3. The ability of D-type cyclins to inhibit androgen receptor transactivation was not shared with other cyclins, and cyclin D1 was as effective as dominant negative mutants of the androgen receptor in inhibiting transactivation. This function of cyclin D1 was independent of its role in cell cycle progression and is likely elicited through its ability to form a specific complex with the androgen receptor. These data underscore the various mechanisms through which the androgen receptor is regulated and also point to a negative feedback role for cyclin D1 in controlling androgen-dependent growth.
Knudsen
K E
KE
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla 92093-0660, USA.
Cavenee
W K
WK
Arden
K C
KC
D002453:Cell Cycle / Q000235:genetics; D019938:Cyclin D1 / Q000378:metabolism*; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism*; D005246:Feedback; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
C534696:CCND3 protein, human; D056743:Cyclin D3; D016213:Cyclins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D019938:Cyclin D1; D017430:Prostate-Specific Antigen