Cell & Molecular Biology Graduate Group

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Joe Kissil
Assistant Professor, The Wistar Institute

Address

308 Wistar Institute (Office)
306 Wistar Institute (Lab)
3601 Spruce Street
Philadelphia, PA 19104-4268

Office tel.: 215 898-3874
Lab tel.: 215 898-2357
Fax: 215 898-3792
E-mail: jkissil@wistar.upenn.edu

Research Interests

Key words: Ras, Rac, Neurofibromatosis type 2, NF2, merlin.

Description of Research

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.

Currently, we are focusing on the crosstalk between Rac and Ras regulated pathways employing a conditional model of lung cancer. By combining conditional activation of K-ras with conditional deletion of Rac1, we demonstrated that Rac1 is required for tumorigenesis. We are examining what pathways downstream of Rac1 are required for K-ras-induced transformation. We have also recently found a 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 functions as a negative regulator of Rac signaling through its direct inhibitory function on p21-activated kinase 1. We are assessing whether this function is indeed the tumor suppressive function of merlin and whether targeting the p21-activated kinases would be beneficial as a treatment modality for neurofibromatosis type 2.

Selected Publications

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.

Kissil J.L., Walmsley, M.J, Hanlon, L., Haigis, K.M., Bender-Kim, C.F., Sweet-Cordero, A., Eckman, M.S.,Tuveson, D.A., Tybulewicz, V.L.J., Jacks, T. “Requirement for Rac1 in a K-ras-induced lung cancer in the mouse.” (2007) Cancer Res. 67:8089-94.

Yi, C., Wilker, E.W., Yaffe, M.B., Stemmer-Rachamimov, A. and Kissil, J.L. “Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2." (2008) Cancer Res. (in press).

Lab

Rotation Projects

Please contact Dr. Kissil Directly about current rotation projects.

Lab personnel:

Scott Troutman - Lab manager
Chunling Yi - Postdoctoral fellow
Linda Hanlon - Postdoctoral fellow
Mi-young Cho - Postdoctoral fellow
Jackie Ellis - CAMB Graduate student