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Identification of domains of c-Jun mediating androgen receptor transactivation
S C Wise1, L A Burmeister, X F Zhou
1University of Toledo, Department of Biology, Ohio 43606, USA.
Abstract:
The proto-oncoprotein c-Jun, when complexed with c-Fos, forms the climeric complex identified as AP-1 which regulates transcription directly by binding to AP-1-responsive genes. We have previously reported an indirect mechanism by which c-Jun is able to regulate transcription by stimulating androgen receptor transactivation in the absence of c-Fos or any apparent DNA binding. A series of c-Jun mutants were tested in order to characterize the domains of c-Jun responsible for this effect. The studies reported here indicate that a functional bZIP region and a portion of the N-terminal activation functions is necessary for c-Jun stimulation of androgen receptor transactivation. Testing c-Jun/v-Jun chimeras, we show that v-Jun is unable to stimulate androgen receptor transactivation and the effect is dependent on the c-Jun activation functions. c-Jun exhibits a bell-shaped activity on androgen receptor-mediated transactivation which appears to be distinct from c-Jun's transactivation ability. A c-Jun mutant deficient in transactivation is able to stimulate androgen receptor activity. These results indicate that c-Jun's transactivation ability can be separated from c-Jun's ability to stimulate the androgen receptor transactivation.
Insights
The proto-oncoprotein c-Jun indirectly stimulates androgen receptor transactivation via its activation functions, independent of its DNA-binding ability. This study identifies key c-Jun domains essential for this distinct regulatory mechanism.
Area of Science:
- Molecular Biology
- Oncogenesis
- Gene Regulation
Background:
- The proto-oncoprotein c-Jun, as part of the AP-1 complex, regulates gene transcription via DNA binding.
- Previously, an indirect mechanism of c-Jun regulating transcription by stimulating androgen receptor (AR) transactivation was reported, independent of c-Fos or DNA binding.
Purpose of the Study:
- To characterize the specific domains of c-Jun responsible for stimulating androgen receptor transactivation.
- To investigate the role of c-Jun's transactivation ability in this indirect mechanism.
Main Methods:
- Utilized a series of c-Jun mutants to identify critical domains.
- Employed c-Jun/v-Jun chimeras to assess functional differences.
- Analyzed c-Jun's effect on androgen receptor-mediated transactivation using a transactivation-deficient mutant.
Main Results:
- A functional basic leucine zipper (bZIP) region and N-terminal activation functions of c-Jun are necessary for stimulating AR transactivation.
- v-Jun cannot stimulate AR transactivation, highlighting the importance of c-Jun's specific activation functions.
- c-Jun exhibits bell-shaped activity on AR transactivation, distinct from its own transactivation capacity.
- A c-Jun mutant lacking transactivation ability can still stimulate AR activity.
Conclusions:
- c-Jun's ability to stimulate androgen receptor transactivation is separable from its intrinsic transactivation function.
- The N-terminal activation functions of c-Jun are crucial for its indirect regulation of AR.
- This finding reveals a novel, DNA-binding-independent regulatory role for c-Jun in androgen receptor signaling.
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