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c-Jun can mediate androgen receptor-induced transactivation
A Bubulya1, S C Wise, X Q Shen
1Department of Biology, University of Toledo, Toledo, Ohio 43606, USA.
Abstract:
The proto-oncoprotein c-Jun forms as a heterodimer with c-Fos, the transcription factor AP-1. AP-1 regulates transcription through transactivation, a process requiring DNA binding. Here we report an indirect mechanism by which c-Jun can regulate transcription via the androgen receptor. In this process, c-Jun is able to support androgen receptor-mediated transactivation in the absence of an interaction with c-Fos or any apparent DNA binding. This positive effect of c-Jun was dose-dependent. Both exogenously added and endogenously induced c-Jun are able to act on the androgen receptor. Transactivation by the androgen receptor can undergo self-squelching, and this was relieved by transfected c-Jun. Using a time-course experiment, we provide evidence that the c-Jun effect is primary. c-Fos is able to block human androgen receptor activity in both the absence and presence of transfected c-Jun. Using a modified form of the yeast two-hybrid system, we show in Cos cells that c-Jun can interact with the DNA binding domain/hinge region (CD regions) of the androgen receptor. Therefore, we propose that c-Jun functions as a mediator for androgen receptor-induced transactivation.
Insights
The proto-oncoprotein c-Jun indirectly regulates androgen receptor (AR) activity without binding DNA or interacting with c-Fos. c-Jun enhances AR-mediated transcription, suggesting a novel mediator role in gene regulation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The proto-oncoprotein c-Jun typically heterodimerizes with c-Fos to form the transcription factor AP-1.
- AP-1 regulates gene transcription through DNA binding and transactivation.
- The androgen receptor (AR) is a key regulator of gene expression, particularly in prostate cancer.
Purpose of the Study:
- To investigate a novel, indirect mechanism by which c-Jun regulates transcription via the androgen receptor.
- To determine if c-Jun can influence AR-mediated transactivation independently of c-Fos or DNA binding.
Main Methods:
- Utilized a modified yeast two-hybrid system in Cos cells to assess protein interactions.
- Performed dose-response and time-course experiments to evaluate c-Jun's effect on AR activity.
- Investigated the impact of c-Fos on AR and c-Jun interactions.
Main Results:
- c-Jun supports AR-mediated transactivation independently of c-Fos or direct DNA binding.
- The positive effect of c-Jun on AR activity is dose-dependent.
- c-Jun interacts with the DNA binding/hinge region of the androgen receptor.
- c-Jun relieves AR self-squelching and its effect is primary, preceding c-Fos interference.
Conclusions:
- c-Jun acts as a mediator for androgen receptor-induced transactivation through a novel indirect mechanism.
- This finding reveals a new regulatory pathway for AR activity, potentially impacting cancer biology.
- c-Jun's interaction with the AR's CD regions is crucial for this mediating function.
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