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D-type cyclins complex with the androgen receptor and inhibit its transcriptional transactivation ability
K E Knudsen1, W K Cavenee, K C Arden
1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla 92093-0660, USA.
Abstract:
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.
Insights
Cyclin D1 and D3 inhibit androgen receptor activity, a key factor in prostate cell growth. This finding reveals a new negative feedback mechanism for cyclin D1 in controlling prostate cancer progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- D-type cyclins regulate cell cycle, differentiation, and transcription.
- D-type cyclins are crucial for androgen-dependent prostate cell proliferation.
Purpose of the Study:
- To investigate if cyclin D1 directly impacts the transactivation potential of the androgen receptor.
- To understand the role of cyclin D1 in androgen receptor-mediated gene expression.
Main Methods:
- Assessed androgen receptor transactivation of the prostate-specific antigen gene.
- Evaluated the effect of D-type cyclins (cyclin D1, D3) on androgen receptor activity.
- Compared cyclin D1's inhibitory effect with dominant-negative androgen receptor mutants.
Main Results:
- Cyclins D1 and D3 significantly inhibited ligand-mediated androgen receptor transactivation.
- This inhibitory effect was specific to D-type cyclins and not observed with other cyclins.
- Cyclin D1's inhibition was independent of its cell cycle role and likely mediated by direct complex formation with the androgen receptor.
Conclusions:
- Cyclin D1 directly inhibits androgen receptor transactivation, independent of its cell cycle function.
- D-type cyclins, particularly cyclin D1, play a negative feedback role in androgen-dependent prostate cell growth.
- These findings highlight novel regulatory mechanisms of the androgen receptor and its role in prostate cancer.