Abelson murine leukemia virus is a rapidly transforming retrovirus that induces pre-B cell lymphoma and transforms pre-B lymphocytes and NIH 3T3 fibroblasts in vitro. The v-Abl protein tyrosine kinase mediates these responses and transmits signals that stimulate growth and suppress apoptosis and differentiation. All of these signals must be appropriately integrated for transformation to occur. A combination of genetic approaches will be used to determine how v-AbI accomplishes this. We will focus on three areas. A combination of genetic and biochemical approaches will be used to study the role of the v-Abl SH2 domain in mediating signals from v-AbI to downstream mediators. Two mutants will be used, a conditional mutant that is compromised for transformation at 39 degrees celcius, and a mutant that encodes a chimeric v-Abl/v-Src protein that fails to transform cells. In a second aim, we will examine the mechanism by which the COOH terminus of v-Abl affects lymphoid cell transformation. The role of the Ras pathway in this response will be investigated using a genetic complementation strategy and sequences at the extreme COOH terminal end of the protein will be identified using a series of deletion and truncation mutants. The mechanism by which these sequences influence the transformation process will be studied by identifying the cellular targets that are affected by these sequences. In the last aim, we will use a unique weakly oncogenic AbMLV mutant that generates highly oncogenic variants in vivo to understand the selective pressures that affect c-onc gene evolution. The dynamics and complexity of the viral population during the selection process and the role of target cell growth stimulation will be tested to uncover features that control this process. These events are likely to mimic those that occur during the v-onc gene capture and should advance our understanding of the way in which v-onc gene containing viruses arise and induce tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA024220-27
Application #
6876151
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Cole, John S
Project Start
1978-09-01
Project End
2007-03-31
Budget Start
2005-04-08
Budget End
2007-03-31
Support Year
27
Fiscal Year
2005
Total Cost
$300,237
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Yi, Chae-ryun; Rosenberg, Naomi (2008) Mutations affecting the MA portion of the v-Abl protein reveal a conserved role of Gag in Abelson murine leukemia virus (MLV) and Moloney MLV. J Virol 82:5307-15
Yi, Chae-Ryun; Rosenberg, Naomi (2007) Gag influences transformation by Abelson murine leukemia virus and suppresses nuclear localization of the v-Abl protein. J Virol 81:9461-8
Marchlik, Erica; Kalman, Richard; Rosenberg, Naomi (2005) Decreased virus population diversity in p53-null mice infected with weakly oncogenic Abelson virus. J Virol 79:11618-26
Kharas, Michael G; Deane, Jonathan A; Wong, Stephane et al. (2004) Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells. Blood 103:4268-75
Warren, David; Griffin, Deborah S; Mainville, Celine et al. (2003) The extreme carboxyl terminus of v-Abl is required for lymphoid cell transformation by Abelson virus. J Virol 77:4617-25
Unnikrishnan, Indira; Rosenberg, Naomi (2003) Absence of p53 complements defects in Abelson murine leukemia virus signaling. J Virol 77:6208-15
Afar, D E; Han, L; McLaughlin, J et al. (1997) Regulation of the oncogenic activity of BCR-ABL by a tightly bound substrate protein RIN1. Immunity 6:773-82
Parmar, K; Rosenberg, N (1996) Ras complements the carboxyl terminus of v-Abl protein in lymphoid transformation. J Virol 70:1009-15
Raffel, G D; Parmar, K; Rosenberg, N (1996) In vivo association of v-Abl with Shc mediated by a non-phosphotyrosine-dependent SH2 interaction. J Biol Chem 271:4640-5
Wang, L C; Chen, Y Y; Rosenberg, N (1995) Pre-B-cells transformed by ts Abelson virus rearrange kappa and lambda [correction of gamma] genes in early G1. Curr Top Microbiol Immunol 194:355-61

Showing the most recent 10 out of 23 publications