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Molecular and Cellular Biology, March 2008, p. 1947-1963, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01672-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epidermal Growth Factor-Dependent Phosphorylation and Ubiquitinylation of MAGE-11 Regulates Its Interaction with the Androgen Receptor{triangledown}

Suxia Bai and Elizabeth M. Wilson*

Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, and Departments of Pediatrics and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

Received 10 September 2007/ Returned for modification 9 October 2007/ Accepted 7 January 2008

The androgen receptor (AR) is a ligand-activated transcription factor that interacts with coregulatory proteins during androgen-dependent gene regulation. Melanoma antigen gene protein 11 (MAGE-11) is an AR coregulator that specifically binds the AR NH2-terminal FXXLF motif and modulates the AR NH2- and carboxyl-terminal N/C interaction to increase AR transcriptional activity. Here we demonstrate that epidermal growth factor (EGF) signaling increases androgen-dependent AR transcriptional activity through the posttranslational modification of MAGE-11. EGF in the presence of dihydrotestosterone stabilizes the AR-MAGE complex through the site-specific phosphorylation of MAGE-11 at Thr-360 and ubiquitinylation at Lys-240 and Lys-245. The time-dependent EGF-induced increase in AR transcriptional activity by MAGE-11 is mediated through AR activation functions 1 and 2 in association with the increased turnover of AR and MAGE-11. The results reveal a dynamic mechanism whereby growth factor signaling increases AR transcriptional activity through the covalent modification of an AR-specific coregulatory protein. Sequence conservation of the MAGE-11 phosphorylation and ubiquitinylation sites throughout the MAGE gene family suggests common regulatory mechanisms for this group of cancer-testis antigens.

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

{triangledown} Published ahead of print on 22 January 2008.

Molecular and Cellular Biology, March 2008, p. 1947-1963, Vol. 28, No. 6
0270-7306/08/$08.00+0     doi:10.1128/MCB.01672-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Karpf, A. R., Bai, S., James, S. R., Mohler, J. L., Wilson, E. M. (2009). Increased Expression of Androgen Receptor Coregulator MAGE-11 in Prostate Cancer by DNA Hypomethylation and Cyclic AMP. Mol Cancer Res 7: 523-535 [Abstract] [Full Text]  
  • Aprelikova, O., Pandolfi, S., Tackett, S., Ferreira, M., Salnikow, K., Ward, Y., Risinger, J. I., Barrett, J. C., Niederhuber, J. (2009). Melanoma Antigen-11 Inhibits the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 and Activates Hypoxic Response. Cancer Res. 69: 616-624 [Abstract] [Full Text]  
  • Ponguta, L. A., Gregory, C. W., French, F. S., Wilson, E. M. (2008). Site-specific Androgen Receptor Serine Phosphorylation Linked to Epidermal Growth Factor-dependent Growth of Castration-recurrent Prostate Cancer. J. Biol. Chem. 283: 20989-21001 [Abstract] [Full Text]  


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