Research in the lab is focused on understanding the regulation of programmed cell death by the Bcl-2 family of proteins. I have used both transgenic and knockout murine models to study the regulation of cell death by the pro-apoptotic family member Bax. We have demonstrated that Bax deficient mice are completely infertile with aberrant regulation of germ cell death. Thus one major focus in the lab will be to study the molecular basis of germ cell apoptosis and exploit what we learn about germ cell death to develop an in vitro model of spermatogenesis for additional studies of germ cell differentiation. This two pronged approach will provide major insight into the normal regulation of spermatogenesis and the aberrant regulation that is observed in male infertility.

Another area of interest centers on the role for Bax in oncogenesis and hematopoiesis. Of particular interest are recent data supporting an important role for Bax in the regulation of the G to S transition in cell division. We have shown that overexpression of Bax accelerates the development of lymphoma in p53 deficient mice despite the increased susceptibility of these cells to apoptosis. This result demonstrates that the ability of Bax to stimulate cell division may in some settings contribute to oncogenesis. This contrasts with multiple recent reports which advocate Bax as a tumor suppressor. Thus a second major focus of the lab will be to identify the molecular mechanism by which both Bcl-2 and Bax regulate cellular proliferation and contribute to oncogenesis.


PUBLICATIONS - (See complete publications list at PubMed)

Emerson, D.K., McCormick, M.L., Schmidt, J.A., and Knudson, C.M.* Taurine monochloramine activates a cell death pathway involving Bax and Caspase-9. J Biol Chem 280, 3233-3241, 2005.

Hadzic, T., Li, L., Cheng, N., Walsh, S.A., Douglas R. Spitz, D.R. and Knudson C.M.* The Role of Low Molecular Weight Thiols in T Lymphocyte Proliferation and IL-2 Secretion. Journal of Immunology 175, 7965-7972, 2005.

Cheng, N., Janumyan, Y.M., Didion, L., Van Hofwegen, C., Yang, E. and Knudson, C.M,* Bcl-2 inhibition of T cell proliferation is directly related to prolonged T cell survival. Oncogene- 23, 3770-3780, 2004.

Luke, J.L. Vande Wetering C. and Knudson, C.M.* Lymphoma development in Bax transgenic mice is inhibited by Bcl-2 and associated with chromosomal instability. Cell Death and Differentiation 10, 740-748, 2003.

RESEARCH STAFF Sean Martin sean-martin@uiowa.edu Research Assistant II 1132 ML 319-335-7630 Chris Van de Wetering chris-vandewetering@uiowa.edu Graduate Student 1132 ML 319-335-9203 Oksana Zagorodna oksana-zagorodna@uiowa.edu Graduate Research Assistant 1132 ML 319-335-9203

Agnieszka Wydra, Sean Martin and Oksana Zagorodna (front row) Chris van de Wetering, Michael Knudson and Nicholas Brown (back row)