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Molecular and Cellular Biology, February 2005, p. 1238-1257, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1238-1257.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Melanoma Antigen Gene Protein MAGE-11 Regulates Androgen Receptor Function by Modulating the Interdomain Interaction

Suxia Bai,1 Bin He,1,{dagger} and Elizabeth M. Wilson1*

Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina1

Received 13 August 2004/ Returned for modification 15 September 2004/ Accepted 15 November 2004

Gene activation by steroid hormone receptors involves the recruitment of the steroid receptor coactivator (SRC)/p160 coactivator LXXLL motifs to activation function 2 (AF2) in the ligand binding domain. For the androgen receptor (AR), AF2 also serves as the interaction site for the AR NH2-terminal FXXLF motif in the androgen-dependent NH2-terminal and carboxyl-terminal (N/C) interaction. The relative importance of the AR AF2 site has been unclear, since the AR FXXLF motif interferes with coactivator recruitment by competitive inhibition of LXXLL motif binding. In this report, we identified the X chromosome-linked melanoma antigen gene product MAGE-11 as an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif. Binding of MAGE-11 to the AR FXXLF {alpha}-helical region stabilizes the ligand-free AR and, in the presence of an agonist, increases exposure of AF2 to the recruitment and activation by the SRC/p160 coactivators. Intracellular association between AR and MAGE-11 is supported by their coimmunoprecipitation and colocalization in the absence and presence of hormone and by competitive inhibition of the N/C interaction. AR transactivation increases in response to MAGE-11 and the SRC/p160 coactivators through mechanisms that include but are not limited to the AF2 site. MAGE-11 is expressed in androgen-dependent tissues and in prostate cancer cell lines. The results suggest MAGE-11 is a unique AR coregulator that increases AR activity by modulating the AR interdomain interaction.

* Corresponding author. Mailing address: Laboratories for Reproductive Biology, CB# 7500, Rm. 3340, Medical Biomolecular Research Building, University of North Carolina, Chapel Hill, NC 27599. Phone: (919) 966-5168. Fax: (919) 966-2203. E-mail: emw{at}med.unc.edu.

{dagger} Present address: Baylor College of Medicine, Houston, TX 77030.

Molecular and Cellular Biology, February 2005, p. 1238-1257, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1238-1257.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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