ANDROGEN EFFECTS MEDIATED BY AR AND PROTO-ONCOPROTEINS

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Steroid hormones, induce and maintain differentiation. A prime example of this is androgen, a steroid hormone absolutely required for normal development and maintenance of male sex characteristics. These dramatic effects of androgens on sexual differentiation are mediated by the androgen receptor (AR), a member of the nuclear receptor superfamily. Like all nuclear receptors, the AR acts by binding its specific ligand, androgen, and causing an increase in the rate of DNA transcription of its target genes. However, unlike other nuclear receptors, which are inhibited by the proto-oncoprotein cJun, AR is actually stimulated by cJun. Indeed, recent results from my lab argue strongly that cJun is a coactivator for AR-mediated transactivation. These results are summarized below: i) both exogenous and endogenous cJun mediate AR transactivation; ii) cJun can relieve AR self-squelching; iii) cJun mutant deficient in DNA binding can still mediate AR transactivation; and iv) anti-sense cJun deletion mutant can specifically block cJun-mediated AR transactivation. Therefore, we propose to further study this novel activity of cJun, which we call trans-coactivation. This will be done by studying the following aspects of the hAR-cJun interaction. First, we will look for a cJun role in the regulation of various androgen- responsive genes, which will examine both promoter and chromatin effects on any cJun activity. Secondly, other members of the Jun family and members of the Fos family will be examined for a role in the cJun coactivation with hAR. Thirdly, we will look more closely at some functional domains within hAR and cJun that are essential for the hAR- cJun coactivation. Fourthly, we will determine at what level the cJun effect, and in carrying out this specific aim, we will examine ligand or DNA binding by hAR, or a direct protein-protein interactions between hAR and cJun. Finally, in the last specific aim, we propose experiments to study the mechanism of action of a truncated form of cJun, which, in the anti-sense orientation, can specifically and completely block cJun coactivation with hAR. In view of the potential involvement of AR in prostate cancer and heart disease and the importance of cJun in regulating cell growth, by successfully carrying out the specific aims of this project, we would be opening up a new and important field of molecular biology which will have broad implications to the study of both normal development and the diseased state.