Cushing's disease is generally caused by benign corticotroph adenomas. Although a relatively uncommon condition, Cushing's diesease is accompanied by significant morbidity and mortality due to the excessive secretion fo ACTH and subsequenct hyperplasia of the adrenal glands. The long-term objectives of this proposal are to understand the regulation of proopiomelanocortin (POMC) gene expression in corticotrophs and define the pathogenesis of corticotroph adenoma formation. The first specific aim is to identify the cis-acting DNA elements of the rat POMC gene that are necessary and sufficient for tissue-specific expression in corticotrophs, melanotrophs, and particular neurons. This study will be accomplished by analyzing the cellular expression of deleted rat POMC genes in transgenic mice. To address the question of whether chronic corticotropin-releasing factor (CRF) secretion can cause hyperplasia and ultimately coricotroph adenomas, excess CRF will be produced in both transgenic mice and transkaryotic rats. Transkaryotic rats will harbor transplantable medullary thyroid carcinoma cells that have been stably transfected with a CRF-expression vector. The final specific aim is to determine whether constitutive expression of proto-oncogenes in corticotrophs can cause pituitary adenomas. The c-myc and c-fos proto-oncogene coding sequences will be fused to corticotroph-specific transcriptional regulatory elements from the POMC gene. These fusion genes will then be introduced into the germ line of transgenic mice and their pituitary glands examined histologically for the development of either corticotroph hyperplasia or neoplasia. Insights gained from these studies may be applicable to understanding the biology and pathogenesis of other benign endocrine tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK040457-04
Application #
3240741
Study Section
Endocrinology Study Section (END)
Project Start
1990-01-01
Project End
1993-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Other Domestic Higher Education
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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Low, M J; Liu, B; Hammer, G D et al. (1993) Post-translational processing of proopiomelanocortin (POMC) in mouse pituitary melanotroph tumors induced by a POMC-simian virus 40 large T antigen transgene. J Biol Chem 268:24967-75
Rubinstein, M; Mortrud, M; Liu, B et al. (1993) Rat and mouse proopiomelanocortin gene sequences target tissue-specific expression to the pituitary gland but not to the hypothalamus of transgenic mice. Neuroendocrinology 58:373-80
Asa, S L; Kovacs, K; Hammer, G D et al. (1992) Pituitary corticotroph hyperplasia in rats implanted with a medullary thyroid carcinoma cell line transfected with a corticotropin-releasing hormone complementary deoxyribonucleic acid expression vector. Endocrinology 131:715-20
Liu, B; Hammer, G D; Rubinstein, M et al. (1992) Identification of DNA elements cooperatively activating proopiomelanocortin gene expression in the pituitary glands of transgenic mice. Mol Cell Biol 12:3978-90

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