Melanoma antigen gene protein-A11 (MAGE-11) is a novel androgen receptor (AR) coregulator that interacts with the AR NH2-terminal FXXLF motif and increases AR transcriptional activity through mechanisms that require phosphorylation and monoubiquitinylation. The post-translational modification of MAGE-11 occurs in response to epidermal growth factor signaling and appears to involve cell cycle regulatory proteins. Our studies will determine the mechanisms that underlie the MAGE-11 dependent increase in AR transcriptional activity.
Aim 1 will pursue preliminary evidence that MAGE-11 interacts directly with SRC/p160 and p300 transcriptional coregulators. MAGE-11 shares sequence similarity with the early adenoviral protein E1A, and like E1A, appears to interact directly with p300. We will identify the interaction sites between MAGE-11, p300 and SRC/p160 as a step toward understanding cell signaling targets that modulate AR activation function 1 in the NH2-terminal domain.
Aim 2 pursues evidence for a phosphorylation-dependent interaction between MAGE-11 and the F-box protein Skp2 (S phase kinase-associated protein 2) to test our hypothesis that MAGE-11 functions as a subunit of the SCF (Skp1-cullin-Skp2 F-box) E3 ubiquitin ligase complex. We will determine whether MAGE-11 is a component of a cullin-based E3 ligase complex that provides a link between AR and its transcriptional coactivators. We will determine the function of CHIP (carboxyl-terminus of Hsp70-interacting protein) in the SCF ligase complex and identify and characterize the E3 ligase that ubiquitinates MAGE-11, a modification required for AR coregulator function. Our studies will provide insight into mechanisms whereby AR regulates gene transcription in human cells.
The androgen receptor (AR) is a ligand activated transcription factor that mediates the biological effects of testosterone and dihydrotestosterone. Androgen-dependent transcriptional activation by AR and its coregulators is required for male reproductive development and function. Naturally occurring AR gene mutations in the human population result in the androgen insensitivity syndrome, whereas gain-offunction AR somatic mutations have been identified in clinical specimens of prostate cancer. More recent evidence indicates the AR has an essential role in the function of the female reproductive tract. Thus, understanding mechanisms of human AR function is important to understanding the processes required for normal sex development and reproductive health. Our proposed studies will establish the mechanisms whereby a newly discovered AR coactivator, expressed only In humans and other primates, increases AR transcriptional activity. Understanding the mechanisms by which MAGE-11 enhances AR transcriptional potential could identify potential new therapeutic targets for modulating AR activity to enhance or inhibit human reproduction function.
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|Lagarde, William H; Blackwelder, Amanda J; Minges, John T et al. (2012) Androgen receptor exon 1 mutation causes androgen insensitivity by creating phosphorylation site and inhibiting melanoma antigen-A11 activation of NH2- and carboxyl-terminal interaction-dependent transactivation. J Biol Chem 287:10905-15|
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