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Christopher van de Wetering


Mentor: Michael Knudson, M.D./Ph.D.
Lab Phone: 335-9203

Paradoxical Effects of Bcl-2 Family Members on Tumorigenesis and Chromosomal Instability

The major goal of our work is to understand the mechanism by which members of the Bcl-2 family regulate oncogenesis. Bcl-2 is an oncogene expressed in some B cell lymphomas and functions to prevent cell death. Many genes homologous to Bcl-2 have been discovered and regulate cell death. These regulators of cell death can be organized into two main classes: A) anti-apoptotic (i.e. Bcl-2) and B) pro-apoptotic (i.e. Bax). Previous studies of the pro-apoptotic Bcl-2 family member Bax have implicated it as a tumor suppressor that it acts downstream of p53 to promote cell death and inhibit oncogenesis. However, in our previous studies, Bax deficiency alone or in combination with p53 deficiency did not predispose to cancer. Instead, we have found that increased Bax expression in T cells employing transgenic mice is able to accelerate tumor formation. Although the mechanism by which Bax promotes oncogenesis is not well defined, increased proliferation has been correlated with increased Bax expression. A hallmark of oncogenesis is genomic instability. Microsatellite and chromosomal instability have been observed in nearly all human malignancies and has been described as an "enabling characteristic" that accelerates the formation of tumors by increasing the rates of genetic mutation. In preliminary studies, we found that thymocytes isolated from Lck-Bax transgenic mice were prone to chromosomal instability (gross aneuploidy) and that this phenomenon occurs prior to the onset of obvious tumor formation. The major goal of this project is to examine how expression of Bcl-2 family members (Bax and Bcl-2) regulates genomic instability and their paradoxical effects on tumor development. We are currently applying the use of both cell culture and animal models to examine the molecular basis of these effects.

Abstracts:

Knudson, C.M., Luke, J., Deimerly, L., and van de Wetering, C. Chromosomal Instability Induced by High Levels of Bax. Cold Spring Harbor Programmed Cell Death, Nov 9-13, 2001.

Knudson, C.M., van de Wetering, C., and Luke, J. Paradoxical tumor development and chromosomal instability in Lck-Bax transgenic mice. Oral presentation at American Society for Hematology, Philadelphia, PA, Dec 6-10, 2002.

Publications:

van de Wetering CI, Coleman MC, Spitz DR, Smith BJ, Knudson CM. Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma. Free Radic Biol Med. 2008 Apr 15;44(8):1677-86. Epub 2008 Feb 7. PubMed PMID: 18291119; PubMed Central PMCID:PMC2374742.

van de Wetering CI, Horne MC, Knudson CM. Chromosomal instability and supernumerary centrosomes represent precursor defects in a mouse model of T-cell lymphoma. Cancer Res. 2007 Sep 1;67(17):8081-8. Erratum in: Cancer Res. 2007 Oct 15;67(20):10097. Horne, Mary C [added]. PubMed PMID: 17804719.

Luke JJ, Van De Wetering CI, Knudson CM. Lymphoma development in Bax transgenic mice is inhibited by Bcl-2 and associated with chromosomal instability. Cell Death Differ. 2003 Jun;10(6):740-8. PubMed PMID: 12761582.



Honors and Awards

  • 2006 Molecular & Cellular Biology Retreat - $250 travel award for best poster.