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.
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.
|Chakraborty, A A; Scuoppo, C; Dey, S et al. (2015) A common functional consequence of tumor-derived mutations within c-MYC. Oncogene 34:2406-9|
|Mazurek, Anthony; Park, Youngkyu; Miething, Cornelius et al. (2014) Acquired dependence of acute myeloid leukemia on the DEAD-box RNA helicase DDX5. Cell Rep 7:1887-99|
|Huang, Chun-Hao; Lujambio, Amaia; Zuber, Johannes et al. (2014) CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev 28:1800-14|
|Saborowski, Michael; Saborowski, Anna; Morris 4th, John P et al. (2014) A modular and flexible ESC-based mouse model of pancreatic cancer. Genes Dev 28:85-97|
|Fellmann, Christof; Lowe, Scott W (2014) Stable RNA interference rules for silencing. Nat Cell Biol 16:10-8|
|Jensen, Mads A; Wilkinson, John E; Krainer, Adrian R (2014) Splicing factor SRSF6 promotes hyperplasia of sensitized skin. Nat Struct Mol Biol 21:189-97|
|Weissmueller, Susann; Manchado, Eusebio; Saborowski, Michael et al. (2014) Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor ? signaling. Cell 157:382-94|
|Bolden, Jessica E; Tasdemir, Nilgun; Dow, Lukas E et al. (2014) Inducible in vivo silencing of Brd4 identifies potential toxicities of sustained BET protein inhibition. Cell Rep 8:1919-29|
|Chen, Chong; Liu, Yu; Rappaport, Amy R et al. (2014) MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. Cancer Cell 25:652-65|
|Das, Shipra; Krainer, Adrian R (2014) Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. Mol Cancer Res 12:1195-204|
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