COORDINATE REGULATION OF LIPOGENIC GENE-EXPRESSION BY ANDROGENS - EVIDENCE FOR A CASCADE MECHANISM INVOLVING STEROL REGULATORY ELEMENT-BINDING PROTEINS

To gain more insight into the molecular mechanisms by which androgens stimulate lipogenesis and induce a marked accumulation of neutral lipi ds in the human prostate cancer cell line LNCaP, we studied their impa ct on the expression of lipogenic enzymes. Northern blot analysis of t he steady-state mRNA levels of seven different lipogenic enzymes revea led that androgens coordinately stimulate the expression of enzymes be longing to the two major lipogenic pathways: fatty acid synthesis and cholesterol synthesis, In view of the important role of the recently c haracterized sterol regulatory element binding proteins (SREBPs) in th e coordinate induction of lipogenic genes, we examined whether the obs erved effects of androgens on lipogenic gene expression are mediated b y these transcription factors, Our findings indicate that androgens st imulate the expression of SREBP transcripts and precursor proteins and enhance the nuclear content of the mature active form of the transcri ption factor, Moreover, by using the fatty acid synthase gene as an ex perimental paradigm we demonstrate that the presence of an SREBP-bindi ng site is essential for its regulation by androgens. These data suppo rt the hypothesis that SREBPs are involved in the coordinate regulatio n of lipogenic gene expression by androgens and provide evidence for t he existence of a cascade mechanism of androgen regulated gene express ion.