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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK045423-13
Application #
2144665
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1990-02-15
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
13
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Organized Research Units
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Agarwal, Sunita K; Impey, Soren; McWeeney, Shannon et al. (2007) Distribution of menin-occupied regions in chromatin specifies a broad role of menin in transcriptional regulation. Neoplasia 9:101-7
Colvis, Christine M; Pollock, Jonathan D; Goodman, Richard H et al. (2005) Epigenetic mechanisms and gene networks in the nervous system. J Neurosci 25:10379-89
Vo, Ngan; Klein, Matthew E; Varlamova, Olga et al. (2005) A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc Natl Acad Sci U S A 102:16426-31
Fass, Daniel M; Butler, Jennifer E F; Goodman, Richard H (2003) Deacetylase activity is required for cAMP activation of a subset of CREB target genes. J Biol Chem 278:43014-9
Walters, Melinda J; Wayman, Gary A; Notis, John C et al. (2002) Calmodulin-dependent protein kinase IV mediated antagonism of BMP signaling regulates lineage and survival of hematopoietic progenitors. Development 129:1455-66
Richards, J P; Bachinger, H P; Goodman, R H et al. (1996) Analysis of the structural properties of cAMP-responsive element-binding protein (CREB) and phosphorylated CREB. J Biol Chem 271:13716-23
Shih, H M; Goldman, P S; DeMaggio, A J et al. (1996) A positive genetic selection for disrupting protein-protein interactions: identification of CREB mutations that prevent association with the coactivator CBP. Proc Natl Acad Sci U S A 93:13896-901
Loriaux, M M; Brennan, R G; Goodman, R H (1994) Modulatory function of CREB.CREM alpha heterodimers depends upon CREM alpha phosphorylation. J Biol Chem 269:28839-43