ANDROGEN AND GLUCOCORTICOID REGULATION OF ANDROGEN RECEPTOR CDNA EXPRESSION

Androgen receptor (AR) levels are regulated by androgens, other steroi ds and non-steroidal hormones via complex, tissue-specific processes. Since alterations in receptor levels may influence cellular sensitivit y to androgens, understanding AR regulation is of fundamental and pote ntially therapeutic significance. Tn most target tissues and AR-contai ning cell lines, AR mRNA is We have reconstituted this androgen-mediat ed down-regulation of AR mRNA in COS 1 cells transfected with a human AR cDNA under the control of the cytomegalovirus (CMV) promoter. The s equences mediating receptor mRNA down-regulation are represented withi n the AR cDNA and not within the CMV promoter. Androgenic down-regulat ion of AR cDNA expression was time- and dose-dependent, resembling nat ive AR mRNA down-regulation. In nic regulation of the receptor cDNA wa s not dependent on protein synthesis suggesting that AR and/or another pre-existing protein(s) is involved in this process. In COS 1 cells c o-transfected with androgen and glucocorticoid receptor cDNAs, dexamet hasone mimicked the action of androgen in down-regulating AR mRNA. Thi s response depended on glucocorticoid receptors. Androgen had little e ffect on steady stale levels of AR protein consistent with reports tha t androgen down-regulates AR mRNA but increases AR protein half-life ( Kemppainen et al. (1992) J. Biol. Chem. 267, 968-974; Zhou et al. (199 5) Mel. Endocrinol. 9, 208-218). However, glucocorticoids decreased AR protein levels in cells that co-expressed androgen and glucocorticoid receptors. These results indicate that sequences represented in the A R cDNA mediate AR mRNA down-regulation by both androgens and glucocort icoids. Inhibition of AR mRNA and protein by glucocorticoids suggests that these steroids may modulate androgen action in tissues, such as m ammary gland and prostate, which express both androgen and glucocortic oid receptors.