Abelson murine leukemia virus (Ab-MLV) transformation has long been a valuable model to understand the dynamics by which retroviruses containing v-onc genes induce tumors and transform cells. The virus provides a simple genetic tool to examine the way in which signals that stimulate growth, suppress apoptosis and alter differentiation interface with signals from tumor suppressor genes. Ab-MLV infection of B lineage cells invariably leads to transformation and tumor induction. This is a rapid process: cells infected in vitro begin to divide soon after viral integration and expression of the v-Abl protein, and infected mice succumb 20 to 30 days post infection. Despite this, the road to transformation is not a smooth one. Viral signals that stimulate cell growth and suppress differentiation and apoptosis are countered by a cellular response that promotes apoptosis and erratic growth. Understanding how the virus counters the cellular response and uncovering the pathways that tip the balance in favor of malignant growth will have broad implications for our understanding of malignant disease and illuminate the features that confer oncogenic properties to Ab-MLV and other v-onc gene-containing retroviruses. In the Ab-MLV system, the p53 pathway is inactivated in most transformants, in some instances, the cells acquire p53 mutations and in others, the p53 regulatory protein, p19Arf is down modulated. We are using the virus to understand how signals from the virus counter anti-tumor effects mediated by the host; We will investigate four aims: 1. How does p53 influence the outcome of Ab-MLV infection? 2. How do the products of the Ink4a/Arf locus influence Ab-MLV transformation? 3. How do the p53 and Ink4a/Arf loci affect tumor induction in vivo? 4.: How is the target cell specificity of Ab-MLV controlled?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA033771-22
Application #
6752453
Study Section
Special Emphasis Panel (ZRG1-VR (02))
Program Officer
Cole, John S
Project Start
1983-06-01
Project End
2008-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
22
Fiscal Year
2004
Total Cost
$335,228
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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