The major goal of this work is to understand the mechanism by which members of the Bcl-2 family regulate oncogenesis. The Bcl-2 family of proteins can be divided into two main classes: A) those that promote cell death (Bax, Bak, etc), and those that prevent it (Bcl-2, Bcl-xL, etc). An enabling characteristic of cancer cells that allows them to survive is their ability to evade cell death pathways by the upregulation of anti-apoptotic proteins like Bcl-2. Previous studies in our laboratory employing transgenic mouse models expressing pro-apoptotic Bax in T cells demonstrated an accelerated development of thymic lymphomas regardless of p53 status. Interestingly, other investigators have found Bcl-2 expression can prevent tumor formation. Taken together, these paradoxical findings suggest that Bax and Bcl-2 have novel functions in regulating oncogenesis. A hallmark of oncogenesis is genomic instability which has been observed in nearly all human malignancies and accelerates tumor formation. The current proposal will test the hypothesis that expression of Bax and Bcl-2 regulates genomic instability. We will test our hypothesis by 1) determining the rate on non-clonal chromosomal instability in transgenic mice expressing Bax and Bcl-2, and 2) the rate of allele modification (HPRT, CAD) in in vitro models of Bax and Bcl-2 genomic instability. The results of these studies will contribute greater knowledge of how the Bcl-2 family can regulate genomic instability and apoptosis in transformed cells and will shed important insight into the biology of oncogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA103362-03
Application #
6949536
Study Section
Special Emphasis Panel (ZRG1-MBC-1 (29))
Program Officer
Bini, Alessandra M
Project Start
2003-09-26
Project End
2007-09-25
Budget Start
2005-09-26
Budget End
2007-09-25
Support Year
3
Fiscal Year
2005
Total Cost
$28,908
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
van de Wetering, Christopher I; Coleman, Mitchell C; Spitz, Douglas R et al. (2008) Manganese superoxide dismutase gene dosage affects chromosomal instability and tumor onset in a mouse model of T cell lymphoma. Free Radic Biol Med 44:1677-86
van de Wetering, Christopher I; Horne, Mary C; Knudson, C Michael (2007) Chromosomal instability and supernumerary centrosomes represent precursor defects in a mouse model of T-cell lymphoma. Cancer Res 67:8081-8