Tissue-specific Molecular Determinants of Survival, Apoptosis and Metabolism

Our laboratory is focusing in elucidating tissue-and context-specific roles of molecules that determine cellular survival and function. Interestingly, many of the molecules involved in cancer formation are also involved in obesity and metabolism. Our goal is therefore to understand tissue-specific roles of these complex molecules. Our focus is in caspases, as well as tumour suppressors and oncogenes such as PTEN and myc. Several projects in our lab involve using genetically engineered mice and taking biological, biochemical and molecular approaches to define pathogenic mechanisms of disease. These approaches to clarify tissue-specific molecular mechanisms have wide implications for treatment of type 1 and type 2 diabetes, as well as islet transplantation.

One main area of research in my laboratory is to elucidate genetic determinants of insulin producing pancreatic beta cell growth and apoptosis in healthy states and in diabetes. In type 1 diabetes, beta cells undergo apoptosis from autoimmune mediated islet destruction. In type 2 diabetes, obesity and inflammation are the underlying cause that ultimately lead to gluco- and lipotoxicity of the beta cells. While these two types of diabetes have distinct pathogenesis, beta cell defect and deficiency are features that may utilize common cellular machinery. We use tissuespecific genetic approaches such as the cre-loxP system to analyze the in vivo functions of the critical genes.

PI3K signaling pathway induces a complex pleiotropic biological outcome that is highly context dependent. PTEN is a phosphatase that is a major negative regulator of this important signaling pathway. PTEN, although first discovered as a tumour suppressor, also appears to have critical effects on metabolism and therefore likely plays a key role in the pathogenesis of insulin resistance and type 2 diabetes. Our goal is to understand the molecular mechanism of PTEN type 2 diabetes models.

Link to online journal

Graduate Student(s):

• Linyuan Wang

Selected References:

• Diana Choi* and Minna Woo. Executioners of apoptosis in pancreatic {beta}-cells: not just for cell death. Am J Physiol Endocrinol Metab. 2010 Apr;298(4):E735-41

• Choi D*, Radziszewska A*, Schroer SA, Liadis N*, Liu Y, Zhang Y, Lam PP, Sheu L, Hao Z, Gaisano HY, Woo M. Deletion of Fas in the pancreatic beta-cells leads to enhanced insulin secretion. Am J Physiol Endocrinol Metab. 2009 297(6):E1304-12

• Xiaohong Wu*, Linyuan Wang*,Stephanie Schroer, Diana Choi*, Peter Chen*, Hitoshi Okada, Minna Woo Perinatal Survivin expression is essential for establishment of pancreatic β-cell mass Diabetologia 2009 52(10):2130-41.

• Radziszewska*, S. Schroer, D. Choi*, P. Tajmir. Radulovich N, Ho JC, Wang L, Liadis N, Hakem R, Tsao MS, Penn LZ, Evan GI, and M. Woo. Absence of Caspase-3 protects β-cells from c-Myc induced apoptosis without leading to tumor formation Journal of Biological Chemistry 2009 284(16):10947-56.

• Radziszewska*, D. Choi*, K-T.T. Nguyen*, S.A. Schroer, P. Tajmir, L. Wang*, A. Suzuki, T.W. Mak, G.I. Evan, and M. Woo. PTEN deletion and concomitant c-Myc activation does not lead to tumor formation in pancreatic beta-cells Journal of Biological Chemistry 2009 284(5):2917 -22


• D. Choi*, K. T. Nguyen*, L. Wang*, S. Schroer, A. Suzuki, T. W. Mak and M. Woo The Growth Defect in Hypothalamic PTEN Knockout Mice is not Rescued by Exogenous GH Endocrinology 2008 149(9):4382-6.

• N. Liadis*, L. Salmena, E. Kwan., P. Tajmir, A. Radziszewska*, X. Li, L. Sheu, M. Eweida, S. Xu, H.Y. Gaisano, R. Hakem, and M. Woo. Distinct in vivo roles of Caspase-8 in beta cells in physiological and diabetes models Diabetes 2007 56(9):2302-11

* Trainees under Dr. Woo's supervision