The central goal of Project 2 is to understand the role of alternative splicing in cancer. Cancer cells display extensive qualitative and quantitative dysregulation of splicing, and a subset of the isoforms that are inappropriately expressed can contribute to tumorigenesis. The mechanisms and pathways through which the splicing-factor oncoprotein SRSF1 and related members of the SR protein family transform cells will be investigated. Organotypic culture, as well as orthotopic and transgenic mouse models will be used to study transformation promoted by these splicing factors and their cooperation with other oncogenes in different cancer contexts. How these factors themselves are regulated in normal cells and upregulated in cancer will be addressed. High-throughput methods will be employed to systematically identify the splicing targets of SR proteins in human cells, and selected targets involved in tumorigenesis will be analyzed in detail. Splicing factors that contribute to the distinctive glycolytic metabolism of cancer cells will be identified and characterized, and alternative splicing of pyruvate kinase pre-mRNA will be investigated as a potential therapeutic target by specifically manipulating this process in tumors.

Public Health Relevance

Alternative splicing is a fundamental step in the normal function of genes. This process is globally altered in cancer cells in ways that can contribute to tumor growth. By studying the role of alternative splicing in cancer, unique vulnerabilities of cancer cells may be uncovered that can be exploited therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA013106-41
Application #
8234411
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (O1))
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2012-05-25
Budget End
2012-12-31
Support Year
41
Fiscal Year
2012
Total Cost
$568,687
Indirect Cost
$259,957
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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