Activated TGF-beta family factors signal via dual Type II (TbetaRII) and dual Type I (TbetaRI/Activin-like kinase 5/ALK5) transmembrane serine/threonine kinases receptors and effector Smad transcription factors. While TGF-beta signaling is critical during endocrine pancreas development, whether TGF-beta plays a role in maintaining adult beta-cell function is unclear. Interestingly, TGF-beta levels are elevated in diabetes, diabetes-associated complications, and obesity. Using primary islets and established beta-cell lines, we are examining the role of various TGF-beta isoforms and their respective receptors on the regulation of key pancreatic specific genes. Smad proteins are the established intracellular effectors of TGF-beta signaling and upon TGF-beta ligand binding, the activated TbetaRI/ALK-5 receptors recruit and phosphorylate receptor-Smads, i.e., Smad2 and Smad3. We are examining the roles of various Smad proteins, in the regulation of gene expression specific to the pancreas. TGF-beta signalling is known to suppress proliferation and promote growth arrest, differentiation/apoptosis of cells of the epithelial lineage. However, the role of this pathway in the growth, proliferation, differentiation and death of constituent pancreatic epithelial cells is unknowm. Using primary islets and established pancreatic ductal and beta cell lines, we are examining the role of TGF-beta signaling in these processes. Of particular interest will be the contribution of TGF-beta signaling in regulation of beta cell mass amd beta cell function. We are using primary islets, and established beta cell lines to examine the effects of TGF-beta isoforms, its receptor activation/inactivation, on beta cell mass and beta cell function. In addition the role of downstream Smad proteins is also being investigated. Several parallel approaches will be taken to explore this issue, which will hopefully lead to an improved understanding of the role of this complex signaling pathway in pancreatic development and specifically in regulation of beta cell mass and function. The information gained will be useful to delineate the role of this pathway in diseases of the pancreas.

Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2010
Total Cost
$481,511
Indirect Cost
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Yadav, Hariom; Devalaraja, Samir; Chung, Stephanie T et al. (2017) TGF-?1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis. J Biol Chem 292:3420-3432
Tiano, Joseph P; Springer, Danielle A; Rane, Sushil G (2015) SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor ? coactivator 1-? (PGC-1?) during exercise. J Biol Chem 290:7671-84
Yadav, Hariom; Rane, Sushil G (2015) Dietary fatty acids: Friends or foes? Obesity (Silver Spring) 23:1329
Tiano, Joseph P; Springer, Danielle A; Rane, Sushil G (2015) SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor ? coactivator 1-? (PGC-1?) during exercise. J Biol Chem 290:11431
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Yadav, Hariom; Lee, Ji-Hyeon; Lloyd, John et al. (2013) Beneficial Metabolic Effects of a Probiotic via Butyrate-induced GLP-1 Hormone Secretion. J Biol Chem 288:25088-97
Yadav, Hariom; Rane, Sushil G (2012) TGF-ýý/Smad3 Signaling Regulates Brown Adipocyte Induction in White Adipose Tissue. Front Endocrinol (Lausanne) 3:35
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Lin, Huei-Min; Lee, Ji-Hyeon; Yadav, Hariom et al. (2009) Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem 284:12246-57
Arany, P R; Rane, S G; Roberts, A B (2008) Smad3 deficiency inhibits v-ras-induced transformation by suppression of JNK MAPK signaling and increased farnesyl transferase inhibition. Oncogene 27:2507-12