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Regulation of Alternative Splicing by the EGF-Signalling Pathway

Gabriela Coutinho-Mansfield

 Appointment Period: 2004-2005 / Grant Year: [20]

Gabriela Coutinho-MansfieldI have been studying the effects of (1) abnormalities in the EGF signaling pathway and (2) hnRNP A1 (a key splicing factor that is depleted in erythroleukemia cells in the mouse) in alternative splicing events. Misregulation of EGF signaling components is a known feature of many types of cancer, such as breast and lung. The rationale behind our work is that changes in alternative splicing have been linked to cell physiology, developmental regulation, and cancer. Although changes in alternative splicing of several target pre-mRNA transcripts upon stimulation of growth factors have been reported, the signaling components between the cell surface and the nuclear splicing machinery are yet to be identified.

I have taken advantage of an alternative splicing high-throughput technology developed in my laboratory at UCSD to survey more than 3,000 different isoforms. Our experiments are performed using cells lacking the adaptor protein Gab1 (for the EGF pathway) and hnRNP A1 and hnRNP A1b (depleted in erythroleukemia) in different cell culture conditions. The first part of this work involved the manual annotation of each of these 3,000 isoforms in the mouse into a database of splicing events (http://splice.sdsc.edu). Unraveling the biochemical association between EGF signaling components and alternative splicing may contribute to the understanding of oncogenic pathways that lead to breast and other forms of cancer. Moreover, the identification of in vitro targets for hnRNP A1 will provide model systems for function dissection of the mechanisms associated with the development of erythroleukemia in the mouse.

Zheng CL, Kwon YS, Li HR, Zhang K, Coutinho-Mansfield G, Yang C, Nair TM, Gribskov M, Fu XD. MAASE: an alternative splicing database designed for supporting splicing microarray applications. RNA. (2005) 11:1767-76. PMID: 16251387; PMCID: PMC1370865.

Coutinho-Mansfield GC, Xue Y, Zhang Y, Fu XD. PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation. Genes Dev. (2007) 21:1573-7. PMID: 17606635.

Lin S, Coutinho-Mansfield G, Wang D, Pandit S, Fu XD. The splicing factor SC35 has an active role in transcriptional elongation. Nat Struct Mol Biol. (2008) 15:819-26. PMID: 18641664; PMCID: PMC2574591.