CAG REPEAT OF THE AR GENE AND PROSTATE CANCER

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We have accumulated evidence that specific alleles of the androgen receptor (AR) gene predispose to, and affect progression of prostate cancer. AR alleles vary in the number of CAG repeats found in exon 1 of the gene and shorter alleles are associated with increased prostate cancer risk. The CAG repeat differences translate into different sizes of a corresponding polyglutamine stretch in the transactivation domain (TAD) of the receptor. Little is known about the mechanism by which this variation might affect AR activity and how it might relate to prostate cancer risk. We postulate that the polyglutamine stretch affects AR transactivation activity due to its potential ability to act as a polar, zipper-type, interface during the interaction of the AR protein with other proteins. This interaction could occur either with auxiliary protein factors during the process of target gene transactivation itself, or with other proteins that might sequester the receptor and make it unavailable to bind to DNA. Different sizes of the polyglutamine stretch may thus quantitatively modulate AR function, and consequently, the androgen responses of prostate cells. Our first aim, therefore, is to quantify the effects of different sizes of the polyglutamine stretches on the transactivation activity of the AR. To this end, we propose to measure the transactivation activity of ARs containing different-sized polyglutamine TADs in prostate cell culture systems in which the activity will be reported by a chromosome- integrated reporter gene under control of prostate- and androgen- specific response elements. Our second aim is to identify, clone, and characterize the unknown nuclear auxiliary protein factor(s) that mediate the effects of the AR on target genes. To this end, the yeast two-hybrid system will be utilized in conjunction with a portion of the AR TAD containing a long polyglutamine stretch. We will then be able to compare the ability of the normal and "at risk" polyglutamine sizes (found in men with advanced prostate cancer) to interact with such proteins.