The present competitive renewal extends our earlier theme of speafic mechanisms of trophic hormone control of key sterol-metabolizing genes in ovarian cells. Granulosa cells in the dominant Graafian follide undergo progressive steroidogenic cytodifferentiation in preparation for the luteal-phase production of progesterone. Concomitantly, theca cells provide limiting androgen substrate required for aromatization to estrogen. Estrogen and progesterone act coordinately to mature the endometrium for implantation of the blastocyst and time the preovulatory gonadotropin surge. Both sex steroids originate from cholesterol's conversion to pregnenolone after sterol uptake and rate-limiting delivery to mitochondnal enzymes. Our recent studies document synergistic drive by LH and the potent insulin-like growth factor, IGF-l, of expression of the low-density lipoprotein-receptor (LDL-R) and steroidogenic acute regulatory protein (StAR) genes in vitro primary cultures of (swine) granulosa and theca cells. Indeed, both genes are under strong transcriptional control. Their products are pivotal to direct the cellular uptake of sterol substrate and its rate-limiting delivery to the inner mitochrondial leaflet. Concomitantly, we could demonstrate predominant expression of the LDL-R gene in granulosa-luteal cells and of the StAR gene in theca cells in vivo Accordingly, we doned their 5'-upstream regulatory regions, and, by promoter deletional analyses, have begun to map cis-acting DNA regions mediating the supraadditive effects of LH and IGF-l. Based on this platform, we propose the following new hypotheses to explicate bihormonal control of sterol-regulatory gene expression in the granulosa-luteal and theca cell: Hypothesis (1). LH and IGF-l achieve synergism by reciprocally amplifying selected facets of distal effector-signaling pathways. Hypothesis (2). LH and IGF-l upregulate LDL-R gene expression supraadditively in the granulosa-luteal cell by way of discrete cis-acting DNA regions and corresponding nuclear transactivating proteins. Hypothesis (3). LH and IGF-I drive StAR gene expression synergistically in theca cells by stimulating distinct cis-acting DNA elements and associated transacting nuclear factors. In ensemble, the foregoing thesis of bihormonal control of sterol-metabolizing gene expression in the granulosa-luteal and theca cell should provide novel insights into how the pituitary gonadotropin, LH, and the locally produced growth factor, IGF-l, act convergently to govern (a) intracellular signaling and (b) gene expression in ovarian cells. Understanding such fundamental interactions is important to the rational design of alternative strategies to interrupt normal and rescue impaired steroidogenesis in the maturing Graafian follicle and corpus luteum.
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