P3K, RETROVIRAL ONCOGENE AND HOMOLOG OF PI 3-KINASE

Scripps Research Institute, La Jolla CA

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Abstract

DESCRIPTION: The avian sarcoma virus ASV 16 contains a new oncogene, p3k, that is homologous to the gene encoding the catalytic subunit of PI 3-kinase. ASV 16 induces oncogenic transformation in chicken embryo fibroblast cultures and hemangiosarcomas in the animal. The work proposed in this application uses the retroviral vector RCAS to express and replicate various mutants of p3k and its targets. It will define the structural and functional consequences of the mutations that activate the oncogenic potential in viral p3k. It will also mark and characterize downstream targets of the viral P3k protein, tracing the signal via the cytoplasmic serine-threonine kinase Akt to genes that are differentially regulated and that determine the neoplastic phenotype of the p3k-transformed cells. A long range goal is to show that differential expression of key targets accounts for the tumorigenic properties of the transformed cell. Angiogenesis is a critical factor in the development of p3k-induced hemangiosarcomas. It will be analyzed in vivo and in vitro. These experiments will seek to elucidate the mechanisms of p3k-induced angiogenesis, deciding between autocrine and paracrine stimulation and identifying angiogenic factors.