Oncogenic activity of alternative splicing factors

Krainer, A. R., Karni, R. (March 2006) Oncogenic activity of alternative splicing factors. Faseb Journal, 20 (4). A456-A456. ISSN 0892-6638

URL: http://www.fasebj.org/cgi/content/meeting_abstract...

Abstract

Alternative splicing plays an important role in cancer, partly by modulating the expression of many oncogenes and tumor suppressors. We have tested the hypothesis that some of the factors that regulate these alternative-splicing events are themselves involved in cancer. We found that the splicing factor SF2/ASF and its antagonist hnRNP A1 are upregulated in different sets of human tumors. In addition, slight overexpression of SF2/ASF is sufficient to transform immortal rodent cells, which can then form tumors in nude mice. The increased expression of SF2/ASF modulates the sensitivity to apoptotic stimuli, and stimulates cell proliferation. In addition, SF2/ASF overexpression results in activation of downstream components of the PI3K/Akt/mTOR and Ras/MAPK signaling pathways, i.e., phosphorylation of S6K1 and eIF4E, respectively. Inhibition of mTOR by rapamycin is sufficient to block the transformation of cells by SF2/ASF overexpression. As expected from its biochemical activities, SF2/ASF overexpression affects alternative splicing of transcripts from many endogenous genes, including a number of tumor suppressors and oncogenes. One of the targets is S6K1 pre-mRNA, resulting in increased expression of a novel isoform with oncogenic activity. These findings demonstrate that an alternative splicing factor can act as a potent oncogene, and suggest that inhibition of mTOR could have a therapeutic benefit in tumors that upregulate SF2/ASF.

Item Type: Paper
Additional Information: Meeting Abstract
Subjects: diseases & disorders > cancer
Publication Type > Meeting Abstract
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:
Communities: CSHL labs > Krainer lab
Depositing User: Matt Covey
Date: March 2006
Date Deposited: 11 Dec 2013 20:40
Last Modified: 18 Apr 2018 19:56
URI: http://repository.cshl.edu/id/eprint/28905

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