Abelson murine leukemia virus (Ab-MLV) is a rapidly transforming retrovirus that contains the oncogene v-abl. Expression of this or other oncogenic forms of abl induces transformation of many types cells and stimulates the growth and differentiation of others. In addition, expression of abl can be lethal. All of these effects are mediated by a single product, which in the case of Ab-MLV, is called Abelson protein. This molecule is a member of the non-receptor protein tyrosine kinase family and the protein tyrosine kinase activity is required for any of the effects of Ab-MLV on cell growth. Although the mechanism by which Abelson protein alters cellular growth most certainly involves tyrosine phosphorylation of cellular proteins, very little is known about the actual pathways involved. The experiments proposed here address this issue in five ways. First, we will use genetically engineered and biologically selected viruses to understand the role of particular portions of the protein in the transformation of lymphoid cells in vivo and in vitro and in the lethal response. Second, we will continue our efforts to isolate dominant negative transformation mutants. Third, we will use the most informative mutants identified in the first two parts of the study to understand the way in which the mutations alter Abelson protein function. Fourth, we will build on our recent observation that an active Abelson protein is required for transformed pre-B cells to transit the G1 phase of the cell cycle. Finally, we will use pre-B lymphocytes transformed by conditional mutants of Ab-MLV to understand the relationship between transformation and differentiation in the Ab-MLV system. Together these experiments will help determine the mechanism by which activated ab/ genes alter cellular growth and differentiation.
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