The control of gene expression at the post-transcriptional level is a fundamental problem in biology, with relevance to cancer. The mechanisms for the regulation of alternative splicing of cellular and viral genes will be investigated, focusing on global mechanisms that affect the expression of large sets of pre -mRNAs in different tissues, developmental stages, and/or in response to external signals. Three families of human alternative splicing factors will be investigated: (I) the SF7 factors, exemplified by the recently identified SF7A protein; (ii) the hnRNP A/B proteins, of which the best characterized is hnRNP A1; and (iii) the SR proteins, whose prototype is SF2/ASF. The SR proteins function also as constitutive splicing factors, but this project will focus on their ability to modulate alternative splicing in vivo and in vitro in a concentration- dependent manner. This activity is antagonized by hnRNP A/B proteins to modulate alternative 5' splice site selection, and by SF7 proteins to determine alternative 3' splice site selection. The molecular mechanisms by which individual members of these families of RNA-binding proteins modulate alternative splice site selection, and how they achieve substrate specificity, will continue to be studies using biochemical, molecular, and reverse genetic approaches. In addition, the hypothesis that specific pairwise combinations of these antagonistic factors are used to regulate alternative splicing of specific sets of pre-mRNAs will be tested, and experiments are proposed to identify natural, specific pre-mRNA targets for regulations by each of these proteins in vivo. These studies are directly relevant to the overall goals of the program project. As global regulators of alternative pre-mRNA splicing, the SR, hnRNP A/B, and SF7 proteins are excellent candidates to account for the observed aberrant patterns of mRNA expression of numerous genes in transformed cells. Among potential targets of these regulators are several critical genes involved in the establishment or maintenance of the transformed phenotype, or in progression of malignancy. Regulation of alternative splicing is responsible for generating oncongenic and non-oncognic forms of many cellular and viral oncogenes. Therefore, a abetter understanding of the basic mechanisms of alternative splicing regulation, and of the specificity of this process, may lead, in the long term, to the identification of drugs that specifically affect the synthesis of particular protein isoforms that play critical roles in tumorigenesis.
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