Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

Wang, Z. X., Chatterjee, D., Jeon, H. Y., Akerman, M., Vander Heiden, M. G., Cantley, L. C., Krainer, A. R. (2012) Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. Journal of Molecular Cell Biology, 4 (2). pp. 79-87.

URL: http://www.ncbi.nlm.nih.gov/pubmed/22044881
DOI: 10.1093/jmcb/mjr030

Abstract

Alternative splicing of the pyruvate kinase M gene (PK-M) can generate the M2 isoform and promote aerobic glycolysis and tumor growth. However, the cancer-specific alternative splicing regulation of PK-M is not completely understood. Here, we demonstrate that PK-M is regulated by reciprocal effects on the mutually exclusive exons 9 and 10, such that exon 9 is repressed and exon 10 is activated in cancer cells. Strikingly, exonic, rather than intronic, cis-elements are key determinants of PK-M splicing isoform ratios. Using a systematic sub-exonic duplication approach, we identify a potent exonic splicing enhancer in exon 10, which differs from its homologous counterpart in exon 9 by only two nucleotides. We identify SRSF3 as one of the cognate factors, and show that this serine/arginine-rich protein activates exon 10 and mediates changes in glucose metabolism. These findings provide mechanistic insights into the complex regulation of alternative splicing of a key regulator of the Warburg effect, and also have implications for other genes with a similar pattern of alternative splicing.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon splicing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Proteomics Service
CSHL labs > Krainer lab
Watson School > Publications
CSHL Cancer Center Shared Resources > Mass Spectrometry Service
Depositing User: Matt Covey
Date: 2012
Date Deposited: 17 Jan 2013 19:26
Last Modified: 30 Oct 2015 14:43
PMCID: PMC3493165
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27076

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