? DESCRIPTION (provided by applicant): We will examine the link between alternate splicing due to Splicing Factor 1 (SF1) and development of colon and testicular germ cell tumors (also known as testicular cancer). Alternate splicing is the process by which exons of primary transcripts (pre-mRNAs) are spliced in different arrangements to produce structurally and functionally distinct mRNAs and protein variants. The majority of mammalian genes undergo alternate splicing and it is estimated that most genes encode at least two different protein variants. This allows cells to generate enormous protein diversity starting from about 30,000 genes. The protein diversity is necessary for fine-tuning cell function and its responses to changing physiological conditions. However, to date, the role of most splicing factors and the function of different spliced variants of genes are unknown. In my laboratory, we found that deficiency of SF1 in Sf1+/- mice causes decreased incidence of testicular tumors. This result was surprising because Sf1+/- mice have higher incidence of carcinogen induced colon tumors. This suggests that SF1 has opposite consequences in different organs, that is, lower SF1 levels protect against testicular cancers but promote colon cancers. To establish the genetic role of SF1 in colon tumorigenesis, our first aim is to test whether SF1 deficiency also increases colon tumor development in genetically predisposed mice. Therefore, we will generate Sf1+/-;ApcMin/+ mice and examine these SF1 deficient ApcMin/+ mice for changes in incidence or characteristics of intestinal polyps. The results will ascertain the genetic contribution of SF1 an establish a new model system for colon tumor studies. To date, only a few alternately spliced targets of SF1 have been identified from cell lines. However, the nature and function of the alternate spliced transcripts due to SF1 in vivo is largely unknown. To address this knowledge gap, we will perform transcriptome profiling using RNA-Seq to identify the global alternate spliced transcripts from the colon and testes of Sf1 deficient mice. Genetic studies lead us to hypothesize that SF1 induced alternately spliced variants are predominantly oncogenic in nature in the testes but tumor suppressor- like in the colon. Identification and comparison of the alternate spliced transcripts will test our hypothesis and provide fundamental insights into how qualitative differences in alternative splicing function of SF1 in the colon and testes relate to te differential effects of SF1 on tumorigenesis. Very little is known about the role of individual splicing factors in cancers. The SF1 deficient mice provide an unprecedented model to conduct exploratory studies on the opposing biological outcome of SF1 in the colon and testes.

R21CA186033

2014-12-02

2018-11-30