Abstract

The applicant's long-term objective is to elucidate the pathways that determine the pattern of neuropeptide synthesis in neural crest-derived tumors. Expression of vasoactive intestinal polypeptide (VIP) in pheochromocytoma and neuroblastoma cells is regulated by cAMP and protein kinase C-dependent pathways. The two questions that will be addressed are 1) How do second messenger systems regulate expression of the VIP gene and 2) Why is expression of the VIP gene restricted to neural crest-derived cells? During the first grant period, a 25 base pair element within the promotor region of the VIP gene was identified, which is required for stimulation of VIP synthesis of cAMP.
The specific aims of the current proposal are to define the structural requirements for the cAMP-responsive element, to determine whether the element is an enhancer, a promoter, or some other kind of regulatory sequence, to characterize specific proteins that bind to the element, to determine whether the cAMP-responsive element mediates the effects of other second messenger systems, and to determine whether there are cis-acting elements within the VIP gene that permit expression only in neural crest-derived tissues. Understanding the mechanisms by which classical second messengers and other trans-acting factors regulate VIP production may help explain why some neural crest-derived tumors produce VIP.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037370-09
Application #
3175213
Study Section
Endocrinology Study Section (END)
Project Start
1990-02-15
Project End
1992-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
Oregon Health and Science University
Department
Type
Other Domestic Higher Education
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239

  Publications

Woloshin, P I; Walton, K M; Rehfuss, R P et al. (1992) 3',5'-cyclic adenosine monophosphate-regulated enhancer binding (CREB) activity is required for normal growth and differentiated phenotype in the FRTL5 thyroid follicular cell line. Mol Endocrinol 6:1725-33
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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