The applicant is currently a junior faculty member at the University of Michigan Medical School who has already demonstrated a long time commitment to a career in academic gastroenterology. Over the past few years he has been conducting his research under the mentorship of Dr. Tadataka Yamada. He has been exploring the possibility that some of somatostatins inhibitory actions on cellular functions might be mediated by inhibition of expression of early response genes. c-fos and c-jun are among the best characterized members of this family of genes. Their products are known to interact with each other to form a heterodimeric transcription factor complex (AP-1) that binds specifically to DNA elements of the consensus sequence TGACTCA and stimulates the transcription of nearby promoters. Both c-fos and c-jun appear to take part in several programs of cellular activation that include growth and differentiation and numerous reports have confirmed that inhibition of c-fos and c-jun activity leads to inhibition of cell proliferation. The ability of somatostatin to inhibit the expression of c- fos and c-jun and thereby inhibit gene transcription activated through AP-l (or TPA response-elements, TRE), might then reflect an important mechanism by which at least some of somatostatin's inhibitory actions on cells, such as proliferation or secretion, might be mediated. This project has important implications not only in the arena of basic science research but also in the field of clinical medicine since somatostatin is currently widely used for the treatment of numerous human diseases. In his initial studies, the PI has demonstrated that somatostatin inhibits both c-fos and c-jun gene expression and AP-l binding and function via activation of multiple protein phosphatases. He has also demonstrated that this effect of somatostatin is paralleled precisely by the ability of the hormone to inhibit both cell proliferation and gastric acid secretion.
The first aim of the present application will be directed at further examining the effect of somatostatin on c-fos and c-jun gene expression by defining the presence of somatostatin response elements in the promoters of these two genes. An attempt will be made to overcome the inhibitory effect of somatostatin on cell function by overexpressing c-fos and c-jun. Finally, studies will be conducted to define a target gene for the inhibitory action of somatostatin on c-fos and c-jun gene expression in the stomach. In particular, once the promoter of the histamine H2-receptor gene contains a putative AP- l site and since histamine is an important gastric acid secretagogue, it will be examined whether somatostatin is able to inhibit histamine H2-receptor gene expression through its inhibitory effect on AP-l.
The second aim will focus on the possibility that somatostatin stimulated protein phosphatases could inhibit protein kinases that activate c-fos and c-jun or lead to dephosphorylation of specific portions of the c-fos and c-jun molecules resulting in diminished gene transcription.
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| 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 |
| Todisco, A; Pausawasdi, N; Ramamoorthy, S et al. (2001) Functional role of protein kinase B/Akt in gastric acid secretion. J Biol Chem 276:46436-44 |
| Chupreta, S; Du, M; Todisco, A et al. (2000) EGF stimulates gastrin promoter through activation of Sp1 kinase activity. Am J Physiol Cell Physiol 278:C697-708 |
| Pausawasdi, N; Ramamoorthy, S; Stepan, V et al. (2000) Regulation and function of p38 protein kinase in isolated canine gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 278:G24-31 |
| Merchant, J L; Du, M; Todisco, A (1999) Sp1 phosphorylation by Erk 2 stimulates DNA binding. Biochem Biophys Res Commun 254:454-61 |
| Todisco, A; Ramamoorthy, S; Pausawasdi, N et al. (1999) Carbachol activates IkappaB kinase in isolated canine gastric parietal cells. Biochem Biophys Res Commun 261:877-84 |
| Takeuchi, Y; Pausawasdi, N; Todisco, A (1999) Carbachol activates ERK2 in isolated gastric parietal cells via multiple signaling pathways. Am J Physiol 276:G1484-92 |
| 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 |
| Todisco, A; Takeuchi, Y; Yamada, J et al. (1997) Molecular mechanisms for somatostatin inhibition of c-fos gene expression. Am J Physiol 272:G721-6 |
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