The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism

Clower, C. V., Chatterjee, D., Wang, Z. X., Cantley, L. C., Heiden, M. G. V., Krainer, A. R. (February 2010) The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism. Proceedings of the National Academy of Sciences of the United States of America, 107 (5). pp. 1894-1899. ISSN 0027-8424

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Abstract

Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production. This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase, in contrast to the M1 isozyme normally expressed in differentiated cells, and it confers a proliferative advantage to tumor cells. The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons. We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues, tumor cell lines, and during terminal differentiation of muscle cells, and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms. We further show that the M1-specific exon is actively repressed in cancer-cell lines-although some M1 mRNA is expressed in cell lines derived from brain tumors- and demonstrate that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to this control. Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production. These findings extend the links between alternative splicing and cancer, and begin to define some of the factors responsible for the switch to aerobic glycolysis.

Item Type: Paper
Uncontrolled Keywords: aerobic glycolysis cancer RNA splicing ALLOSTERIC REGULATION BINDING-PROTEIN TUMOR-GROWTH CANCER GENE M2 ISOZYMES
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
School of Biological Sciences > Publications
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: CSHL Librarian
Date: 2 February 2010
Date Deposited: 28 Sep 2011 14:39
Last Modified: 05 Jan 2018 19:36
PMCID: PMC2838216
Related URLs:
URI: https://repository.cshl.edu/id/eprint/15393

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