The long-term objective of this research is to identify the intracellular signaling pathways that are critical for oncogenic transformation by altered forms of the ABL tyrosine kinase. Oncogenic forms of ABL are linked to the development of human, murine and feline leukemias. Activation of ABL may occur as a consequence of chromosomal translocations. The chimeric BCR-ABL oncogene is produced by a reciprocal chromosomal translocation that fuses varying amounts of the BCR gene on chromosome 22 with sequences upstream of the second exon of the c-ABL gene on chromosome 9. Three different BCR-ABL proteins may be produced: P210 which is the causative agent of greater than 95 percent of chronic myelogenous leukemia (CML). P185 which is associated with a subset of acute lymphocytic leukemias (ALL), and P230 which is associated with chronic neutrophilic leukemia (CNL), a rare myeloproliferative disorder characterized by a mild hematologic phenotype. The P185 and P210 forms of BCR-ABL have been proposed to transform cells through their ability to enhance cell proliferation, block apoptosis, alter cell adhesion and increase cell motility. Multiple proteins have been identified as downstream targets of BCR-ABL. However, only a small subset of these proteins have been shown to play critical roles in the biological activities associated with BCR-ABL expression.
The specific aims of this proposal are: 1) to test the hypothesis that the ubiquitin-dependent degradation of specific cellular proteins by the oncogenic BCR-ABL tyrosine kinases constitutes a novel mechanism for the functional inactivation of growth inhibitors/tumor suppressors, and 2) to identify intracellular signaling pathways that are differentially regulated by the oncogenic forms of BCR-ABL (such as P210) and by the weakly leukemogenic P230 protein that is associated with an indolent or benign clinical disease. Comparative analysis of the BCR-ABL proteins may allow the identification of critical molecular components required for malignant transformation by BCR-ABL. Furthermore, our finding that oncogenic tyrosine kinases trigger the destruction of specific target proteins via the ubiquitin proteasome machinery provides a potentially important pathway for the elimination of growth inhibitors/tumor suppressors during tumor progression. Definition of this pathway may allow for the development of therapeutic reagents for the treatment of leukemias and other cancers that are caused by the activation of nonreceptor tyrosine kinases.
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