Mechanisms by which steroid hormone receptor levels and functionality are controlled represent the focus of these studies. Model systems will be used in which we can examine receptor regulation by steroid hormones themselves, by peptide hormones, and by a class of compounds that may directly interfere with nuclear interactions of steroid-receptor complexes. The first system utilizes estrogen- and androgen-responsive tissues of the rat (primarily uterus, ventral prostate and anterior pituitary) to probe the dynamics of estrogen and androgen receptor turnover as influenced by the respective favored classes of steroid hormones themselves. A key feature of these studies at their present stage of development is the painstaking and systematic analysis of fluctuations in all populations of intracellular receptor. An off- shoot of this work has been the description of a discrete set of high affinity microsomal binding sites that are specific for steroid hormones and appear to mask microsomal acceptor sites for classical steroid-receptor complexes, thus being capable of regulating intranuclear levels of these complexes. In the next phase of these investigations, we will define acceptor specificity, explore the function of the microsomal binders as receptors for elicitation of extra-genomic actions of steroids, and, using monoclonal antibodies to the estrogen receptor, probe the origin and turnover of these proteins. Localization within specific organelles and initial attempts at purification will also be undertaken. The second major system, receptor control by peptide hormones, will continue to be addressed by the prolactin-mammary gland estrogen receptor interplay. We will use viral infection studies to investigate a correlation between levels of MMTV expression and sensitivity of mammary tissue to prolactin as a regulator of estrogen receptor activity. We will continue to study the mechanism by which prolactin regulates these receptors, concentration on differential nuclear binding affinities of prolactin-induced vs direct-estrogen-induced receptors, under conditions where graded responses can be engendered. We will begin to look for other factors involved in receptor regulation in this tissue. The third system involves modulation of steroid-receptor complex interactions at the nuclear level by agents which may interact directly with DNA to alter receptor binding to its effector sites. We have at hand a natural product that prevents formation of estrogen-responsive populations of mammary tumors by regulating receptor activity without direct interaction with the receptor. This may represent a novel form of receptor activity regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK032046-10
Application #
3230530
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1982-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1993-03-31
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Hendry, L B; Chu, C K; Rosser, M L et al. (1994) Design of novel antiestrogens. J Steroid Biochem Mol Biol 49:269-80
Hendry, L B; Chu, C K; Copland, J A et al. (1994) Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes. J Steroid Biochem Mol Biol 48:495-505
Copland, J A; Hendry, L B; Chu, C K et al. (1993) Inhibition of estrogen stimulated mitogenesis by 3-phenylacetylamino-2,6-piperidinedione and its para-hydroxy analog. J Steroid Biochem Mol Biol 46:451-62
Steinsapir, J (1992) Microsomal steroid receptors in target tissues. Receptor 2:45-76
Hendry, L B; Mahesh, V B (1992) Stereochemical complementarity of progesterone, RU486 and cavities between base pairs in partially unwound double stranded DNA assessed by computer modelling and energy calculations. J Steroid Biochem Mol Biol 41:647-51
Hendry, L B; Mahesh, V B (1991) Stereochemical complementarity of progesterone and cavities between base pairs in partially unwound double stranded DNA using computer modeling and energy calculations to determine degree of fit. J Steroid Biochem Mol Biol 39:133-46
Steinsapir, J; Muldoon, T G (1991) Role of microsomal receptors in steroid hormone action. Steroids 56:66-71
Steinsapir, J; Mora, G; Muldoon, T G (1991) Effects of steroidal and non-steroidal antiandrogens on the androgen binding properties of the rat ventral prostate androgen receptor. Biochim Biophys Acta 1094:103-12
Wood, J C; Copland, J A; Muldoon, T G et al. (1991) 3-phenylacetylamino-2,6-piperidinedione inhibition of rat Nb2 lymphoma cell mitogenesis. Proc Soc Exp Biol Med 197:404-8
Evans Jr, A C; Muldoon, T G (1991) Characterization of estrogen-binding sites associated with the endoplasmic reticulum of rat uterus. Steroids 56:59-65

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