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Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism

Yi, Wen and Clark, Peter M. and Mason, Daniel E. and Keenan, Marie C. and Hill, Collin and Goddard, William A., III and Peters, Eric C. and Driggers, Edward M. and Hsieh-Wilson, Linda C. (2012) Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism. Science, 337 (6097). pp. 975-980. ISSN 0036-8075. PMCID PMC3534962. http://resolver.caltech.edu/CaltechAUTHORS:20120918-075521218

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Abstract

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1126/science.1222278DOIArticle
http://www.sciencemag.org/content/337/6097/975.abstractPublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534962/PubMed CentralArticle
http://dx.doi.org/10.1126/science.1227513Featured InScience: Perspective
http://cen.acs.org/articles/90/i35/Glycosylation-Linked-Cancer.htmlFeatured InC&EN: News of the Week
http://dx.doi.org/10.1038/nchembio.1077Featured InNature Chemical Biology: Research Highlights
http://dx.doi.org/10.1126/scisignal.2003530Featured InScience Signaling: Editors' Choice
ORCID:
AuthorORCID
Goddard, William A., III0000-0003-0097-5716
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Alternate Title:PFK1 Glycosylation Is a Key Regulator of Cancer Cell Growth and Central Metabolic Pathways
Additional Information:© 2012 American Association for the Advancement of Science. Received for publication 22 March 2012. Accepted for publication 29 June 2012. We thank P. Qasba for the Y289L GalT construct, R. Abrol for computational modeling advice, R. Diamond for cell cycle analysis, and L. Cantley and M. Vander Heiden for useful discussions. This work was supported by the National Institutes of Health (grant R01 GM084724 to L.C.H-W), the Department of Defense Breast Cancer Research Program (grant W81XWH-10-1-0988 to W.Y), and a Tobacco-Related Disease Research Program Postdoctoral Fellowship (19FT-0078 to W.Y). We also thank Agios Pharmaceuticals for financial support in providing patient tumor and matched tissue samples.
Funders:
Funding AgencyGrant Number
NIHR01 GM084724
Department of Defense Breast Cancer Research ProgramW81XWH-10-1-0988
Tobacco Related Disease Research Program Postdoctoral Fellowship19FT-0078
Agios Pharmaceutical UNSPECIFIED
PubMed Central ID:PMC3534962
Record Number:CaltechAUTHORS:20120918-075521218
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20120918-075521218
Official Citation:Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism Wen Yi, Peter M. Clark, Daniel E. Mason, Marie C. Keenan, Collin Hill, William A. Goddard III, Eric C. Peters, Edward M. Driggers, and Linda C. Hsieh-Wilson Science 24 August 2012: 975-980.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:34161
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:18 Sep 2012 15:29
Last Modified:01 Mar 2019 17:42

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