Estradiol administration initiates rapid and dramatic growth responses in the uterus. This growth requires the coordinated control and sequential increase in expression of many genes. Although it has been shown that estradiol increases very early proto-oncogene expression in the ovariectomized rat uterus, the relationship of these inductions to uterine mitogenic responses in specific uterine tissues has not been determined. We propose that estrogens elicit their effects in causing uterine cell proliferation through the increased expression of proto-oncogenes. To elucidate the role of oncogene expression in steroid-induced uterine responses, the following specific aims are proposed to examine the kinetics of induction, the tissue location, and hormonal control of uterine proto-oncogene expression. (1) Uterine mRNA's encoding c-jun, jun B, jun D, c-fos, c-ski and c-myc will be quantitated at short intervals after estradiol treatment of ovariectomized mature rats. With the kinetics of the inductions established, the hormone specificity and dose responses of the inductions will be determined. (2) In situ hybridization and immunohistochemistry will be used to identify the specific uterine cell types expressing each proto-oncogene. (3) To determine whether altered proto-oncogene expression is a primary response to estradiol, the sensitivity of increases in mRNA levels of cycloheximide and actinomycin D will be determined. (4) The mechanisms by which estradiol increase proto- oncogene expression will be examined by determining the effects of the hormone on rates of transcription and on levels of mRNA translational activity. (5) Treatments with short acting estrogens which initiate only early uterine responses will be used to examine the functions of proto-oncogene expression in early components of the response to estradiol. Treatment with progesterone which redirects the tissue location of uterine responses estradiol will be used to examine the tissue specificity of proto-oncogene expression. The information gained from these proposed studies will enable us to examine the biochemical function of oncogene products in the uterine response to estradiol. Improved understanding of these mechanisms will enhance our capability of controlling normal uterine physiology and cancer cell proliferation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD022918-05
Application #
3322859
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1987-04-01
Project End
1993-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Nephew, K P; Polek, T C; Khan, S A (1996) Tamoxifen-induced proto-oncogene expression persists in uterine endometrial epithelium. Endocrinology 137:219-24
Akcali, K C; Khan, S A; Moulton, B C (1996) Effect of decidualization on the expression of bax and bcl-2 in the rat uterine endometrium. Endocrinology 137:3123-31
Wang, H; Peters, G A; Zeng, X et al. (1995) Yeast two-hybrid system demonstrates that estrogen receptor dimerization is ligand-dependent in vivo. J Biol Chem 270:23322-9
Nephew, K P; Peters, G A; Khan, S A (1995) Cellular localization of estradiol-induced c-fos messenger ribonucleic acid in the rat uterus: c-fos expression and uterine cell proliferation do not correlate strictly. Endocrinology 136:3007-15
Nephew, K P; Tang, M; Khan, S A (1994) Estrogen differentially affects c-jun expression in uterine tissue compartments. Endocrinology 134:1827-34
Nephew, K P; Polek, T C; Akcali, K C et al. (1993) The antiestrogen tamoxifen induces c-fos and jun-B, but not c-jun or jun-D, protooncogenes in the rat uterus. Endocrinology 133:419-22
Webb, D K; Moulton, B C; Khan, S A (1993) Estrogen induces expression of c-jun and jun-B protooncogenes in specific rat uterine cells. Endocrinology 133:20-8
Nephew, K P; Webb, D K; Akcali, K C et al. (1993) Hormonal regulation and expression of the jun-D protooncogene in specific cell types of the rat uterus. J Steroid Biochem Mol Biol 46:281-7
Cho, F S; Phillips, K S; Khan, S A et al. (1993) Cloning of the rat cyclin-dependent kinase 4 cDNA: implication in proliferation-dependent expression in rat tissues. Biochem Biophys Res Commun 191:860-5
Bloch, C A; Ozbun, M A; Khan, S A (1993) Glycogen phosphorylase: developmental expression in rat liver. Biol Neonate 63:113-9

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