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.
Androgen receptor dependent gene transcription is required for male and female reproductive health. Studies outlined in this proposal seek to establish the mechanisms controlling androgen receptor function. Our focus is understand how of a newly discovered androgen receptor specific coregulatory protein, known as MAGE11, links the androgen receptor to cell cycle regulatory proteins that are required for both male and female reproductive development and function.
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