Benjamin de Haas explains individual differences in eye movement patterns.
New Research In
Physical Sciences
Featured Portals
Articles by Topic
Biological Sciences
Featured Portals
Articles by Topic
Communicated by Tom Maniatis, Harvard University, Cambridge, MA, December 22, 2009 (received for review December 2, 2009)
↵1C.V.C. and D.C. contributed equally to this work.
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.
Footnotes
- 2To whom correspondence should be addressed. E-mail: krainer{at}cshl.edu.
Author contributions: C.V.C., D.C., Z.W., L.C.C., M.G.V.H., and A.R.K. designed research; C.V.C., D.C., Z.W., and M.G.V.H. performed research; C.V.C., D.C., Z.W., L.C.C., M.G.V.H., and A.R.K. analyzed data; C.V.C., D.C., Z.W., L.C.C., M.G.V.H., and A.R.K. wrote the paper.
The authors declare a conflict of interest. L.C.C. and M.G.V.H. are associated with Agios Pharmaceuticals.
- Cynthia V. Clowera,1,
- Deblina Chatterjeeb,c,1,
- Zhenxun Wangb,d,
- Lewis C. Cantleya,
- Matthew G. Vander Heidena,e,3, and
- Adrian R. Krainerb,c,d,2
- aDivision of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
- bCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;
- cGraduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794;
- dWatson School of Biological Sciences, Cold Spring Harbor, NY 11724; and
- eDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115
Communicated by Tom Maniatis, Harvard University, Cambridge, MA, December 22, 2009 (received for review December 2, 2009)
↵1C.V.C. and D.C. contributed equally to this work.
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.
- aerobic glycolysis
- cancer
- RNA splicing
Footnotes
- 2To whom correspondence should be addressed. E-mail: krainer{at}cshl.edu.
Author contributions: C.V.C., D.C., Z.W., L.C.C., M.G.V.H., and A.R.K. designed research; C.V.C., D.C., Z.W., and M.G.V.H. performed research; C.V.C., D.C., Z.W., L.C.C., M.G.V.H., and A.R.K. analyzed data; C.V.C., D.C., Z.W., L.C.C., M.G.V.H., and A.R.K. wrote the paper.
The authors declare a conflict of interest. L.C.C. and M.G.V.H. are associated with Agios Pharmaceuticals.
The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism
Sign up for Article Alerts
Article Classifications
- Biological Sciences
- Biochemistry
Jump to section
You May Also be Interested in
The distant rock has offered clues about planet formation and the state of the early solar system.
Image credit: Wikimedia Commons/NASA/Johns Hopkins University Applied Physics Laboratory/Southwest Research Institute/ESA.
Researchers report negative emotional contagion, or the coordination of emotional states between multiple individuals, in common ravens, suggesting convergent emotional evolution in birds and mammals.
Image courtesy of Jessie E. C. Adriaense.
A study examines trends in global fishing fleets and finds that by 2015, 68% of the global fishing fleet became motorized, and that the overall number of fleet vessels increased to 3.7 million, despite a consistent decrease in the catch per unit of effort.
Image courtesy of Pixabay/3282700.
A method to determine gender from fingerprints suggests pottery making was not a primarily female activity in ancient Puebloan society, challenging previous assumptions about gendered divisions of labor in ancient societies.
Image courtesy of John Kantner.