Objective
Cancer is a multifaceted disease involving numerous mutations in many tumor suppressors and oncogenes. Elucidation of the molecular basis of cancer has been and continues to be a major goal of biomedical research in the past few decades. Previous evidence suggests a connection between alternative splicing and cancer, and the activities of many oncogenes and tumor suppressors are modulated by alternative splicing. We found recently that the splicing factor SF2/ASF is a potent proto-oncogene, capable of transforming immortal and primary fibroblasts when slightly overexpressed. We found that SF2/ASF is upregulated in a set of human tumors and SFRS1, the gene coding for SF2/ASF is specifically amplified in some breast tumors but not in normal breast tissue from the same patient. Moreover, we identified several endogenous splicing targets of SF2/ASF, among them a novel oncogenic isoform of the mTOR substrate, S6K1, which is essential for SF2/ASF-mediated transformation. Based on these findings, we propose to study the detailed mechanisms of SF2/ASF-mediated transformation in cancer. We will dissect the specific functions of SF2/ASF required for its activity as an oncoprotein, through a structure-function analysis of its specific domains, using deletion mutants that are impaired in specific biological processes. We hypothesize that the splicing activity of SF2/ASF is essential for its transforming activity. Thus, we wish to identify and validate the regulated alternative splicing targets of SF2/ASF. We will identify these splicing targets on a genome-wide scale, using an exon array recently developed by Affymetrix. These experiments will shed light on the molecular mechanisms by which SF2/ASF is upregulated in human cancer and can lead to transformation. The analysis of a novel type of proto-oncogene has the potential to uncover new molecular aspects of cancer, and to provide new opportunities for diagnosis and therapy.
Fields of science
Not validated
Not validated
Call for proposal
FP7-PEOPLE-2007-4-3-IRG
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Funding Scheme
MC-IRG - International Re-integration Grants (IRG)Coordinator
91904 Jerusalem
Israel