Abstract

The overall objective of this work is to elucidate the mechanism by which specific environmental signals stimulate human pheochromocytoma cells in tissue culture to synthesize and secrete vasoactive intestinal peptide (VIP), a neuropeptide that is not present in normal adrenal medulla but occasionally appears as an ectopic hormonal secretion of pheochromocytoma. Hypersecretion of VIP in man causes the """"""""watery/diarrhea hypokalemia, achlorhydria syndrome."""""""" Study of the hormonal regulation of gene expression in pheochromocytoma may provide a system by which factors determining ectopic hormone biosynthesis in neuroendocrine tissues in general may be elucidated. In preliminary studies, it was found that pheochromocytomas maintained in culture develop the ability to produce and secrete VIP. Production of VIP in these cells is regulated by nerve growth factor (NGF) and dexamethasone. During the first phase of this project, the optimum conditions for studying VIP production at the molecular level will be established, including determining the time courses and dose response curves for the effects of NGF and dexamethasone and evaluating the influence of serum components on VIP production. A complimentary DNA molecule encoding the precursor of VIP will then be constructed and used to determine whether the culture conditions, NGF, or dexamethasone are acting at a transcriptional or translational level to influence VIP synthesis. Finally, the VIP gene itself will be examined for features associated with active gene expression, allowing comparison of these features in tissues which have the potential to produce VIP given the appropriate environmental signals. (C)

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037370-02
Application #
3175208
Study Section
Endocrinology Study Section (END)
Project Start
1984-03-01
Project End
1987-02-28
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
2
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code

  Publications

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Walton, K M; Rehfuss, R P; Chrivia, J C et al. (1992) A dominant repressor of cyclic adenosine 3',5'-monophosphate (cAMP)-regulated enhancer-binding protein activity inhibits the cAMP-mediated induction of the somatostatin promoter in vivo. Mol Endocrinol 6:647-55
Rehfuss, R P; Walton, K M; Loriaux, M M et al. (1991) The cAMP-regulated enhancer-binding protein ATF-1 activates transcription in response to cAMP-dependent protein kinase A. J Biol Chem 266:18431-4
Fink, J S; Verhave, M; Walton, K et al. (1991) Cyclic AMP- and phorbol ester-induced transcriptional activation are mediated by the same enhancer element in the human vasoactive intestinal peptide gene. J Biol Chem 266:3882-7
Tsukada, T; Fink, J S; Mandel, G et al. (1987) Identification of a region in the human vasoactive intestinal polypeptide gene responsible for regulation by cyclic AMP. J Biol Chem 262:8743-7
Tischler, A S; Dayal, Y; Balogh, K et al. (1987) The distribution of immunoreactive chromogranins, S-100 protein, and vasoactive intestinal peptide in compound tumors of the adrenal medulla. Hum Pathol 18:909-17
Goodman, R H; Leiter, A; Low, M J et al. (1987) Biosynthesis of pancreatic islet hormones. Hepatology 7:36S-41S
Lechan, R M; Wu, P; Jackson, I M et al. (1986) Thyrotropin-releasing hormone precursor: characterization in rat brain. Science 231:159-61
Tsukada, T; Horovitch, S J; Montminy, M R et al. (1985) Structure of the human vasoactive intestinal polypeptide gene. DNA 4:293-300
Leiter, A B; Montminy, M R; Jamieson, E et al. (1985) Exons of the human pancreatic polypeptide gene define functional domains of the precursor. J Biol Chem 260:13013-7

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