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Characterizing the oncogenic properties and target genes of the splicing factor protooncogene SF2ASF

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.

Field of science

  • /medical and health sciences/clinical medicine/cancer/breast cancer

Call for proposal

FP7-PEOPLE-2007-4-3-IRG
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Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

THE HEBREW UNIVERSITY OF JERUSALEM
Address
Edmond J Safra Campus Givat Ram
91904 Jerusalem
Israel
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 100 000
Administrative Contact
Eran Vardi (Dr.)