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J Mol Cell Biol. 2012 Apr;4(2):79-87. doi: 10.1093/jmcb/mjr030. Epub 2011 Nov 1.

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

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  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

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.

PMID:
22044881
[PubMed - indexed for MEDLINE]
PMCID:
PMC3493165
Free PMC Article

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