The general goals of this proposal relate to three major areas: I, The study of the physiological significance of cytoplasmic (RcII) and nuclear type II (RnII) estrogen binding sites and an endogenous ligand (EL-II) which bind to these sites. The effects of estrogen on estrogen receptor binding and nuclear accumulation will be examined in relation to the stimulation of RcII and RnII sites and EL-II. The interaction of EL-II and similar compounds (Doisynolic acids) with cytosol and nuclear type I (estrogen receptor) and type II sites will be evaluated and related to uterotropic responses. In addition, the relationship between type I and II sites and EL-II will be studied during development of the female reptoductive tract. These studies should provide insight into the mechasnisms which control cellular proliferation and abnormal cell growth. II. The study of the physiological significance and characterization of triphenythylene antiestrogen binding sites (TABS) and an endogenous ligand for these sites (TABS-EL). TABS will be characterized in both solid tissues and serum with respect to cellular localization, LDL-receptor ,LDL-cholesterol and cholesterol metabolism and effects of hormonal controls on this system. TABS-EL will be purified and identified and its biological action will be examined as it relates to cholesterol metabolism. The interactions of clomiphene and tamoxifen with TABS and TABS-EL will also be studied. These studies should provide new information concerning the mechanism of action of antiestrogenic drugs and the involvement of endogenous effectors on this function. III. Further characterization and purification of the receptor activation factor (RAF). Purification of RAF will be performed in order to establish the importance of this factor in nuclear binding of the estrogen receptor, RNA polymerease activity, DNA-dependent ATP-ase activity and DNA helix destabilization. The physiological significance of RAF and its relationship to other steroid hormone receptors will also be examined. RAF may be a key component of the estrogen receptor which contains the enzymatic activity necessary for activation of the target tissue genome and hence, understanding its mechanism if action should have broad application to both basic and clinical science.
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