Pro-opiomelanocortin (POMC) is encoded by a single copy gene. POMC gene transcription occurs in several tissues, notably in the pituitary anterior and intermediate lobes and in the hypothalamus. A POMC-like mRNA is also made in the gonads. In the male, the mRNA is found in Leydig cells, the same cells which contain immunoreactive POMC peptides. Gonadal POMC mRNA is much shorter than its counterpart in pituitary, and in fact lacks part of the sequence which encodes the amino-terminal glycopeptide. These data suggest that gonadal POMC gene transcription initiates at a different site in the gene than does the pituitary transcript, and gives rise to a structurally different protein. This finding raises questions about hormonal regulation of POMC gene expression in the gonads. In particular, what are the effects of glucocorticoids on Leydig cell POMC gene activity? These steroid hormones are potent inhibitors of both transcription of the gene and secretion of the peptides in the anterio pituitary. Because Leydig cells seem to have functional glucocorticoid receptors, a comparison of the steroid hormones action on the POMC gene in Leydig and pituitary cells provides a natural model for further defining molecular mechanisms involved in steroid hormone action. In doing so it may give new insight into biochemical links between the stress response and reproductive systems, as well as expand our knowledge of a substance (the steroid hormone) which is one of the most widely used pharmacological agents. Moreover, while there is much known about interactions between the glucocorticoid-receptor complex and DNA sequences in and around genes whose expression is stimulated by the hormone, little is known about steroid-hormone inhibition of gene activity. Therefore, the present study should provide new insights into this mode of hormone action. The proposed studies will use cloned DNA probes in POMC mRNA quantitation studies and in structural analysis of the POMC gene, both in chromatin and in a purified state in the presence of the glucocorticoid-receptor complex. Studies will also examine the structure of Leydig cell POMC protein. In addition, they will determine whether secretion is regulated by agents which affect POMC peptide secretion in other tissues and/or agents which regulate secretion of other substances from Leydig cells.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD018110-05
Application #
3315066
Study Section
Endocrinology Study Section (END)
Project Start
1983-07-01
Project End
1989-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
5
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Eskeland, N L; Schachter, B S (1994) Temperature effect on the action of corticotropin-releasing hormone (CRH) on secretion of immunoreactive beta-endorphin (IR beta EP) in TM3 and AtT-20 cell lines. Life Sci 55:1929-35
Eskeland, N L; Molineaux, C J; Schachter, B S (1992) Regulation of beta-endorphin secretion by corticotropin-releasing factor in the intact rat testis. Endocrinology 130:1173-9
Harlan, R E; Shivers, B D; Fox, S R et al. (1989) Distribution and partial characterization of immunoreactive prolactin in the rat brain. Neuroendocrinology 49:7-22
Eskeland, N L; Lugo, D I; Pintar, J E et al. (1989) Stimulation of beta-endorphin secretion by corticotropin-releasing factor in primary rat Leydig cell cultures. Endocrinology 124:2914-9
Piccinini, L A; Goldsmith, N K; Schachter, B S et al. (1988) Localization of HLA-DR alpha-chain messenger ribonucleic acid in normal and autoimmune human thyroid using in situ hybridization. J Clin Endocrinol Metab 66:1307-15
Nelson, J F; Bender, M; Schachter, B S (1988) Age-related changes in proopiomelanocortin messenger ribonucleic acid levels in hypothalamus and pituitary of female C57BL/6J mice. Endocrinology 123:340-4
Piccinini, L A; Schachter, B S; Davies, T F (1986) HLA-DR alpha chain expression in human thyroid cells. Endocrinology 118:2611-3
Shivers, B D; Harlan, R E; Pfaff, D W et al. (1986) Combination of immunocytochemistry and in situ hybridization in the same tissue section of rat pituitary. J Histochem Cytochem 34:39-43