Publication: Glycolytic enzymes can modulate cellular life span.
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Abstract
An unbiased screen for genes that can immortalize mouse embryonic fibroblasts identified the glycolytic enzyme phosphoglycerate mutase (PGM). A 2-fold increase in PGM activity enhances glycolytic flux, allows indefinite proliferation, and renders cells resistant to ras-induced arrest. Glucosephosphate isomerase, another glycolytic enzyme, displays similar activity and, conversely, depletion of PGM or glucosephosphate isomerase with short interfering RNA triggers premature senescence. Immortalized mouse embryonic fibroblasts and mouse embryonic stem cells display higher glycolytic flux and more resistance to oxidative damage than senescent cells. Because wild-type p53 down-regulates PGM, mutation of p53 can facilitate immortalization via effects on PGM levels and glycolysis.
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Grant support: Wellcome Trust, Medical Research Council, Cancer Research UK,the Marie Curie and the Hugh and Catherine Stevenson Funds, a Marie Curie fellowship (M.E. Lleonart), and a Human Frontiers Science Program fellowship (J. Gil).The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. We thank Drs. Kevin Brindle and K. Uchida for the human phosphofructokinase clone and antibodies, respectively, Dr. H. Arakawa for p53RFP clone, and Dr. Austin Smith and Robin Lovell-Badge for mouse embryonic stem cells. We are also grateful to all the members of David Beach’s laboratory for helpful advice and discussions.
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Cancer Res . 2005;65(1):177-85.