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Gene Expression and Regulation
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Molecular and Cellular Oncogenesis
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Joseph Kissil , Ph.D.

Assistant Professor
Molecular and Cellular Oncogenesis Program
215-898-3874, Office
215-898-3792, Fax
jkissil@wistar.org

Introduction

Our lab is studying signaling networks that relay information from the extra-cellular environment into cells. These signaling pathways are involved in almost every aspect of inter- and intracellular communication and their deregulation often leads to pathological conditions, such as cancer. We are interested in understanding how various pathways communicate with one another, under normal conditions, and how the deregulation of this crosstalk manifests as disease. Towards this goal we apply a variety of tools including animal and cellular model systems.

Research Summary

The main interest of the lab is the understanding of signal transduction networks in vivo and their deregulation in cancer. We are studying the pathways regulated by the small G-proteins K-ras and Rac1 and dissecting the crosstalk between these pathways employing animal models. We are also focusing on the neurofibromatosis type 2 tumor suppressor gene (Nf2) and examining its role in the regulation of Ras/Rac crosstalk and how loss of Nf2 results in cancer. We approach these issues mainly in vivo, by developing animal models harboring specific knock-in mutations in genes of interest. These models are then used to examine the function of these mutations in development and cancer.

Research over the past several years has yielded considerable amounts of information on signal transduction pathways. Major efforts are underway to integrate this data into a comprehensive map of cellular signaling networks. As these efforts progress, it is clear that there are some confounding elements in the data that need to be addressed. One such issue is the fact that these complex pathways are highly sensitive to various experimental factors, including cell type and levels of transgene expression. Thus, it is crucial to examine these signaling events under physiological conditions. To begin a systematic analysis of intracellular signaling in an in vivo context, we are focusing on the p21-Ras protein and pathways downstream of it, centering our attention on the interaction of the Ras and Rac pathways.

The Ras and Rac families of protein are small GTP-binding proteins, which function as molecular switches. The Ras-proteins were originally identified as oncogenes and their role in transformation and cancer is well established. They regulate an extensive number of cellular processes through a few signaling pathways, including the PI3-kinase, MAP-kinase, Ral-GDS and Rac pathways. The Rac proteins are members of the Rho family of small G-proteins, and are also implicated in the regulation of several pathways, including those leading to cytoskeleton reorganization, gene expression, and endocytosis. Recent work has demonstrated that Rac signaling is required for Ras-signal transduction and transformation. The role of Rac family proteins in cancer is not clear. While tumor-associated mutations in the Rho family genes have not been reported, the overall activity of Rac1 and cdc42 appears to be upregulated in some forms of cancer.

To directly assess the requirement for Rac1 in K-ras induced tumorigenesis in vivo, we employed a conditional model of lung cancer in which an oncogenic allele of K-ras is activated by Cre-mediated recombination. By combining conditional activation of K-ras with conditional deletion of Rac1, we demonstrated that Rac1 is required for tumorigenesis. We are currently examining what pathways downstream of Rac1 are required for K-ras-induced transformation in vivo.

We have recently found an additional possible link between the Rac-signaling pathways and cancer in the case of Neurofibromatosis type 2 (NF2), an inherited disorder that is characterized mainly by development of Schwann cell tumors of the eighth cranial nerve. The Nf2 gene is a tumor suppressor gene coding for a protein called merlin, which is highly homologous to the ERM proteins moesin, ezrin, and radixin. Merlin is regulated by phosphorylation induced by Rac/cdc42 via the p21-activated kinases (Pak1 and 2) and functions as a negative regulator of Rac signaling through its direct inhibitory function on Pak1. We are currently assessing whether this function is indeed the tumor suppressive function of merlin. In addition, we are working on establishing whether targeting the p21-activated kinases would be beneficial as a treatment modality for neurofibromatosis type 2.

Selected Publications

Joseph L. Kissil, Kristen C. Johnson, Matthew S. Eckman and Tyler Jacks. "Merlin phosphorylation by p21-activated kinase 2 and effects of phosphorylation on merlin localization" (2002) Journal of Biological Chemistry, 277(12), 10394-9.

Joseph L. Kissil, Erik C. Wilker, Kristen C. Johnson, Matthew S. Eckman, Michael B. Yaffe and Tyler Jacks. “Merlin, the product of the Nf2 tumor suppressor gene, is as an inhibitor of p21-activated kinase (Pak1)” (2003) Molecular Cell, 12(4), 841-849.

Yi, C., McCarty, JH., Troutman, SA., Eckman, MS., Bronson, RT., and Kissil, JL.

“Loss of the putative tumor suppressor band 4.1B/Dal1 gene is dispensable for normal development and does not predispose to cancer.” (2005) Molecular and Cellular Biology. 25(22):10052-9.


 

Joseph Kissil , Ph.D.


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