Transforming growth factor- beta (TGFbeta) is a potent inhibitor of pancreatic cell proliferation. Disruption of the TGFBeta signaling pathway may be important in the development of pancreatic cancer. Recently, deleted in pancreatic carcinoma 4 (DPC4) was identified as a tumor suppressor gene that is inactivatated in 50% of pancreatic tumors. DPC4 (also known as Smad4) act as signaling molecules in TGFBeta-related signaling pathways. Many human pancreatic cancer cell lines are refractory to the growth inhibitory effects of TGF-beta. In this proposal, we will examine the role of Smad genes in TGFBeta- mediated growth regulation in the pancreas and in the development of pancreatic cancer. We have hypothesized that: 1) Smad genes are required for growth inhibition and regulation of differentiation by TGFBeta in pancreatic acinar and duct cells; 2) TGFBeta modulates Smad acitivity by interacting with other signaling pathways, including the MAP kinaase signaling pathway; 3) dominant negative Smads stably transfected into immortalized pancreatic cells will induce tumorigenesis; and 4) functional inactivation of Smad gnes in the pancreas in a transgenic mouse model results in uncontrolled cell proliferation. It is likely that the results of the proposed studies will reveal valuable insight into TGFBeta- mediated growth regulatory mechanism in the pancreas and the role of Smad proteins in neoplastic transformation of the pancreas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK002637-04
Application #
6476014
Study Section
Special Emphasis Panel (SRC)
Program Officer
Podskalny, Judith M,
Project Start
1999-04-15
Project End
2003-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
4
Fiscal Year
2002
Total Cost
$114,885
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Simeone, Diane M; Zhang, Lizhi; Treutelaar, Mary K et al. (2006) Islet hypertrophy following pancreatic disruption of Smad4 signaling. Am J Physiol Endocrinol Metab 291:E1305-16
Simeone, D M; Zhang, L; Graziano, K et al. (2001) Smad4 mediates activation of mitogen-activated protein kinases by TGF-beta in pancreatic acinar cells. Am J Physiol Cell Physiol 281:C311-9
Zhang, L; Graziano, K; Pham, T et al. (2001) Adenovirus-mediated gene transfer of dominant-negative Smad4 blocks TGF-beta signaling in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 280:G1247-53