We have identified melanoma antigen gene product MAGE-n as an androgen receptor (AR) coregulator thatincreases AR activity in the presence of androgen by modulating steroid receptor pi6o coactivatorrecruitment. Studies outlined in this proposal will determine whether MAGE-n serves as a docking site forAR coregulators in the normal male and female reproductive tract and in polycystic ovarian syndrome(PCOS). Our hypothesis is that MAGE-n modulates AR activity in human ovary and endometrium byfacilitating the recruitment of coregulators to the AR transcription complex through direct and indirectmechanisms. Our studies will establish the temporal pattern of MAGE-n expression over the reproductivecycle in the human and monkey ovary and endometrium. We will establish the function of MAGE-n and ARin the endometrium during the window of receptivity to embryo implantation and explore whether temporalchanges in MAGE-n influence folliculogenesis and maturation by modulating AR signaling. Ourpreliminary studies indicate EGF signaling controls MAGE-n coregulator activity. We will determinethe effects of EGF on phosphorylation and ubiqutinylation of MAGE-n and how these post-transcriptionalmodifications alter interactions between AR and coregulators. We will investigate the structural basisfor naturally occurring mutations in AR and MAGE-n that alter AR function without changing high affinityandrogen binding. A structural relay between the ligand binding pocket and activation function 2 in theligand binding domain that occurs in response to high affinity androgen binding will be characterized todetermine how naturally occurring gene defects can be overcome by selective AR ligands and modulators.
Specific aim i will identify the temporal pattern of expression and hormone regulation of MAGE-n relativeto AR and other AR coregulators in human and monkey ovary and human endometrium and alterations inexpression associated with PCOS.
Specific aim 2 will establish the mechanisms whereby MAGE-iimodulates AR transcriptional activity by acting as a coregulator docking site in normal and PCOS ovary andendometrium.
Specific aim 3 will determine the mechanisms whereby EGF signaling modulates ARtranscriptional activity through phosphorylation and ubiquitinylation of MAGE-ii.
Specific aim 4 willestablish the functional basis for naturally occurring AR mutations that cause the androgen insensitivitysyndrome and determine whether mutations in the MAGE-n gene cause AIS in the male and prematureovarian failure in the female.
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