Alternative Splicing in Normal Development and in Breast Cancer.

Abstract : Alterations in the splicing patterns of key regulatory genes are likely to play an important role in oncogenesis. The ASF/SF2 protein is one of a family of SR splicing factors that have been shown to regulate splice site choice in vitro. We have mapped the ASF/SF2 gene to 17q21.3-q22 in humans, and close to the Ovum mutant locus on chromosome 11 in mice. Our current objective is to examine the role of the ASF/SF2 gene in development and oncogenesis by observing the effects of disrupting the gene in mice. We were unable to achieve germ line transmission using embryonic stem cells that were heterozygous for an ASF/SF2 deletion. Highly chimeric mice were runted, possessed hypotrophic testes, and were sterile. Because of the possibility that this result is due to haploinsufficiency of the ASF/SF2 gene, and in light of new data that suggest that ASF/SF2 may be required for cell viability, we are constructing an inducible knockout vector for the ASF/SF2 gene.