Abelson murine leukemia virus (Ab-MLV) induces a rapid pre-B cell lymphoma in mice and transforms pre-B cells and some established rodent fibroblasts in vitro. This virus carries the v-abl oncogene, a member of the nonreceptor protein tyrosine kinase (PTK) family of oncogenes and transformation is mediated by the PTK activity of the v-Abl protein encoded by Ab-MLV. However this activity alone does not explain the unique spectrum of cellular responses to Ab-MLV. Other features of the protein are critical in determining the outcome of infection. Important v-Abl domains have been defined but the mechanisms by which these regions orchestrate the changes in growth and differentiation that result from Ab- MLV infection are largely unknown. The proline rich COOH terminus of the molecule is unique to Abl proteins and plays an important but poorly understood role in transformation of lymphoid cells. The SH2 domain a region that interacts with tyrosine phosphorylated moieties appears to influence the types of cells susceptible to transformation. Transformation of lymphoid cells involves both malignant growth and differentiation arrest. Experiments with Ab-MLV mutants suggest that distinct pathways mediate these two phenomena. However, our understanding of the circuits by which this and other responses to expression of v-Abl occurs is not well- developed. The work proposed here focuses on understanding these mechanisms by asking four questions: l. What sequences within the COOH terminus of v-Abl protein enhance lymphoid transformation? 2. How do signals to the Ras pathway and other pathways mediate the effects of the COOH terminus on lymphoid cell transformation? 3. How do sequences in SH2 domain of v-Abl protein interact with Shc an adaptor protein that interacts with Grb2/Sos and how do they modulate transformation? 4. What pathways mediate v-Abl induced differentiation arrest? The information obtained should further our understanding of the features that control the response to infection with this virus and also contribute to a broader understanding of the mechanisms by which abl and other oncogenes induce malignant disease.
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