The mechanism by which estrogen induces proliferation of its target cells is poorly understood. Three hypotheses have been proposed: (1), that estrogen acts directly upon the responsive cells; (2) that estrogen induces growth factors which in turn stimulate the responsive cells; and (3) that estrogen neutralizes the action of an inhibitor which blocks the responsive cells from going through the cell cycle. The goal of this proposed research is to explore the third hypothesis. Evidence has already been presented that such a postulated inhibitor exists in mammalian serum, and that it can be specifically neutralized by estrogen. The specific objectives of this proposal are: (1) to at least partially purify and physicochemically characterize the putative inhibitor; (2) to search for the body organ which secretes the inhibitor, and evaluate the relative usefulness of that organ as a starting material vis-a-vis serum for purification; and (3) based on this information, to design a purification protocol for the inhibitor. Long-range plans are to test the validity of the inhibitor hypothesis using purified inhibitor and defined medium.
