Abstract

This is a proposal to continue studies on the properties and function of the gastrin/CCK-B receptor and a putative receptor for Gly-extended gastrin (G-Gly). During the previous funding period, the PI and his collaborators have shown that the Gly-extended intermediate, an obligatory precursor of amidated gastrin, is stored with gastrin and secreted with it in response to physiological stimuli. Gly-extended gastrin was shown to stimulate cell growth via a separate receptor. The binding of the gastrin/CCK-B receptor and the structural requirements for activation of G proteins were also studied. Several key components of transcriptional regulation of the gastrin/CCK-B receptor gene were identified. The present proposal is designed to extend these studies. The following specific aims will be pursued. 1) elucidate the structural components of the gastrin/CCK-B receptor that are important in determining cell growth and secretion; 2) characterize the structural components of the gastrin/CCK-B receptor gene that are important in determining its expression and function; 3) examine the post-receptor events linked to cell growth mediated by Gly-extended gastrin; and 4) further characterize the receptor for Gly-extended gastrin and clone its corresponding cDNA.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK034306-17
Application #
6380497
Study Section
Special Emphasis Panel (ZRG1-RAP (02))
Program Officer
May, Michael K
Project Start
1984-07-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
17
Fiscal Year
2001
Total Cost
$343,197
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Todisco, A; Ramamoorthy, S; Witham, T et al. (2001) Molecular mechanisms for the antiapoptotic action of gastrin. Am J Physiol Gastrointest Liver Physiol 280:G298-307
Sawada, M; Finniss, S; Dickinson, C J (2000) Diminished prohormone convertase 3 expression (PC1/PC3) inhibits progastrin post-translational processing. Regul Pept 89:19-28
Wang, L D; Wang, M; Todisco, A et al. (2000) The human histamine H(2) receptor regulates c-jun and c-fos in a differential manner. Am J Physiol Cell Physiol 278:C1246-55
Stepan, V M; Tatewaki, M; Matsushima, M et al. (1999) Gastrin induces c-fos gene transcription via multiple signaling pathways. Am J Physiol 276:G415-24
Stepan, V M; Dickinson, C J; del Valle, J et al. (1999) Cell type-specific requirement of the MAPK pathway for the growth factor action of gastrin. Am J Physiol 276:G1363-72
Stepan, V M; Sawada, M; Todisco, A et al. (1999) Glycine-extended gastrin exerts growth-promoting effects on human colon cancer cells. Mol Med 5:147-59
Stepan, V M; Krametter, D F; Matsushima, M et al. (1999) Glycine-extended gastrin regulates HEK cell growth. Am J Physiol 277:R572-81
Nagahara, A; Wang, L; Del Valle, J et al. (1998) Regulation of c-Jun NH2-terminal kinases in isolated canine gastric parietal cells. Am J Physiol 275:G740-8
Todisco, A; Takeuchi, Y; Urumov, A et al. (1997) Molecular mechanisms for the growth factor action of gastrin. Am J Physiol 273:G891-8
Ford, M G; Valle, J D; Soroka, C J et al. (1997) EGF receptor activation stimulates endogenous gastrin gene expression in canine G cells and human gastric cell cultures. J Clin Invest 99:2762-71

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