SIGNALING PATHWAYS UTILIZED BY V-ABL AND BCR-ABL

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Mutant forms of the Abelson tyrosine kinase, v-Abl and BCR-ABL, cause malignant transformation in many mammalian species including humans. Understanding the signaling paths utilized by v-Abl and BCR-ABL is key to understanding the mechanisms by which they cause malignancy. The goal of this Program Project is to study three particular aspects of signaling by v-Abl and BCR-ABL. Project #1, led by Dr. Stephen Goff, will study the role of a newly discovered Abl-binding protein, Abi-l is probably important in early signaling events which link Abl tyrosine kinase activity to downstream effectors which link Abl tyrosine activity to downstream effectors, particularly Ras. Project #2 led by Dr. Paul Rothman, will determine the role of the recently discovered activation of Janus kinases (Jaks) by v-Abl. Jaks represent an alternative signaling path, utilized by normal cytokines, which may be important for Abl transformation. Project #3, led by Dr. Kathryn Calame will study recently discovered connections between regulation of cell cycle and V- Abl including vAbl dependent induction of cyclin D mRNA, v-Abl-dependent decrease in p27 protein and p53-dependent inhibition of v-Abl transformation. In each of these projects the molecular mechanisms and functional importance for Abl-dependent transformation of different signaling pathways will be determined. The projects will be supported by three scientific cores and one administrative core. The first Core will provide standardized virus stocks, monoclonal antibodies and Abelson transformed cell lines to all projects. The second Core will provide care and breeding of mice nullizygous for genes involved in the pathways under study. The third Core will supply primary cells from patients with Chronic Myelogenous Leukemia to individual projects, supported by the Cores, will be shared among the projects so that collaborative experiments can be performed to determine how signaling by each of the pathways under study is related to the others. The knowledge gained by this Program Project will not improve our understanding of Abelson-dependent transformation but will also help us understand general mechanisms of oncogenesis and signal transduction.