Mechanism of Androgen Receptor Induced Cytotoxicity

Buck Institute For Age Research, Novato CA

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Abstract

DESCRIPTION (provided by applicant): Kennedy's disease, or spinal and bulbar muscular atrophy (SBMA) is caused by an expansion of CAG repeats (which encode for glutamine) in the 5' end of the coding region of the androgen receptor (AR) gene. It is one of nine polyglutamine repeat diseases that cause the selective loss of neurons in selective regions of the brain. Seven of the polyglutamine repeat proteins, including AR, are substrates for caspases. Therefore it is important to understand the role of caspase activation and proteolysis in polyglutamine repeat-mediated cell death. The specific aims of this proposal are: (1) To determine if the toxic fragments generated by caspase-mediated proteolysis of AR interact with full-length AR and disrupts its function. (2) To determine which protein interaction domains are required for the caspase-7 and AR apoptosome-like complex. (3) To determine which initiator caspases are important in androgen receptor induced cell death.