Pituitary adrenocorticotropic hormone (ACTH) is a major stimulus for glucocorticoid synthesis, and is derived from processing of pro-opiomelanocortin. Dr. Drouin has been working for many years to understand transcriptional control of the POMC gene, and especially the mechanisms of negative feedback exerted by glucocorticoids on POMC. He has characterized two pathways which may mediate glucocorticoid effects on this gene. One involves binding of the glucocorticoid receptor (GR) to a negative glucocorticoid-response element in the gene and the formation of novel receptor:DNA complexes. The other involves target DNA sequences which do not bind GR and thus, must utilize different mechanisms. The proposed research will define the molecular mechanisms responsible for repression through each pathway using POMC- expressing tumor cells, AtT-20 cells. Genetic analysis of promoter sequences and biochemical analysis of in vitro interactions will be used to define these mechanisms at the molecular level. The role of each pathways in vivo will be assessed in transgenic mice. The novel features of glucocorticoid receptor interaction with POMC DNA, and of the dual mechanisms for glucocorticoid repression, indicate that the POMC gene is an excellent paradigm for the understanding of nuclear receptor- dependent repression of transcription.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK048070-01
Application #
2148120
Study Section
Endocrinology Study Section (END)
Project Start
1995-05-01
Project End
1998-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Clinical Research Institute of Montreal
Department
Type
DUNS #
City
Montreal
State
QC
Country
Canada
Zip Code
H2 1-R7
Drouin, J; Maira, M; Philips, A (1998) Novel mechanism of action for Nur77 and antagonism by glucocorticoids: a convergent mechanism for CRH activation and glucocorticoid repression of POMC gene transcription. J Steroid Biochem Mol Biol 65:59-63
Philips, A; Maira, M; Mullick, A et al. (1997) Antagonism between Nur77 and glucocorticoid receptor for control of transcription. Mol Cell Biol 17:5952-9
Philips, A; Lesage, S; Gingras, R et al. (1997) Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17:5946-51