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A Role of the Amino-Terminal (N) and Carboxyl-Terminal (C) Interaction in Binding of Androgen Receptor to Chromatin

Department of Molecular and Cellular Biology (J.L., J.F., C.T., J.W.), Baylor College of Medicine, Houston, Texas 77030; and Department of Biochemistry and Molecular Biology (H.Y.), Yonsei University College of Medicine, Soedaemoon-gu, Seoul 120-752, Korea

Address all correspondence and requests for reprints to: Jiemin Wong, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: jwong{at}bcm.tmc.edu.

The N-terminal domain of AR is known to engage a hormone-dependent interaction with its C-terminal ligand-binding domain, and this N/C interaction is known to modulate AR transcriptional activity. Using Xenopus oocytes as a model system to study transcriptional regulation in chromatin, we found that two previously reported N/C interaction-defective AR mutants, one with deletion of ²³FQNLF²⁷(ARF) and one with a Gly 21 to Glu mutation (ARG21E), were surprisingly inactive in activating transcription from various reporters assembled into chromatin. Further study using chromatin immunoprecipitation assay revealed that these mutants failed to bind both mouse mammary tumor virus-long terminal repeat and prostate-specific antigen enhancer assembled into chromatin. This defect is specific to chromatin because both mutants could bind to a consensus AR response element in vitro and activate transcription driven by mouse mammary tumor virus-long terminal repeat in transient transfection as effective as the wild-type AR. To further substantiate this novel finding, we established 293 cell lines that stably expressed either AR or ARF mutant in an inducible manner. Using these cell lines, we confirmed by using chromatin immunoprecipitation assay that AR but not ARF could bind to the endogenous prostate-specific antigen enhancer. Furthermore, we found that the ARF mutant interacts poorly with Brg1, the ATPase subunit of the chromatin-remodeling factor SWI/SNF. Taken together, our study reveals a novel role of AR N/C interaction in control of AR chromatin binding and suggests a working model that the proper N/C interaction is required for AR to recruit SWI/SNF complex, which in turn remodels chromatin to allow AR to bind to AR response elements in chromatin.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   p300  |  SRC-1  |  AIB1

Ligands:   R1881

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