In all mammalian species, reproductive success is critically dependant upon normal function of the ovary. Normal ovarian function serves two purposes, production of the oocyte, and appropriate production and secretion of specific steroid and protein hormones. In the mammalian ovary, the oocyte is encased in several layers of cells which secrete the female sex steroid hormone estrogen. At ovualation, the oocyte is extruded from the ovary and the cells which previously surrounded the oocyte are changed into a structure called the corpus luteum. The cells of the corpus luteum, the luteal cells, secrete the female sex steroid hormone, progesterone. The secretion of progesterone from the corpus luteum in the proper amounts for the proper time period is required for successful reproduction. Thus, progesterone secretion from the corpus luteum is a critical determinant of reproductive success. The cells of the corpus luteum must respond, through biochemical mechanisms, to blood born hormonal substances which control the normal secretion of progesterone. The specific biochemical mechanisms which allow the luteal to respond to those hormones which control progesterone secretion are at present unknown. It is, in fact, these mechanisms that are responsible for normal luteal function. Dr. Goldsmith has recently discovered that, in the rat, the expression of a particular gene, the K-ras gene, increases greatly at the same time that the seretion of progesterone from the corpus luteum is at its maximum. Furthermore, when an antibody against the protein coded for by this gene was incorporated into luteal cells in vitro, progesterone secretion from these cells was significantly decreased, thus demonstrating that the protein encoded by the K-ras gene, the p21 protein, plays a role in the production/secretion of progesterone by the luteal cell. It is the objective of this proposal to determine the specific way in which the p21 protein affects luteal progesterone secretion and whether the p21 protein plays a role in the secretion of other hormones from the corpus luteum. The K-ras gene product, the p21 protein, is present in all mammalian cells. Thus, the results of the proposed studies will have a significant impact upon the understanding of ovarian hormone secretory mechanisms as well as our understanding of the ways in which all mammalian cells respond to hormones and growth factors.
