Document Detail

Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle.
MedLine Citation:
PMID:  21402913     Owner:  NLM     Status:  MEDLINE    
During cell proliferation, the abundance of the glycolysis-promoting enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3), is controlled by the ubiquitin ligase APC/C-Cdh1 via a KEN box. We now demonstrate in synchronized HeLa cells that PFKFB3, which appears in mid-to-late G1, is essential for cell division because its silencing prevents progression into S phase. In cells arrested by glucose deprivation, progression into S phase after replacement of glucose occurs only when PFKFB3 is present or is substituted by the downstream glycolytic enzyme 6-phosphofructo-1-kinase. PFKFB3 ceases to be detectable during late G1/S despite the absence of Cdh1; this disappearance is prevented by proteasomal inhibition. PFKFB3 contains a DSG box and is therefore a potential substrate for SCF-β-TrCP, a ubiquitin ligase active during S phase. In synchronized HeLa cells transfected with PFKFB3 mutated in the KEN box, the DSG box, or both, we established the breakdown routes of the enzyme at different stages of the cell cycle and the point at which glycolysis is enhanced. Thus, the presence of PFKFB3 is tightly controlled to ensure the up-regulation of glycolysis at a specific point in G1. We suggest that this up-regulation of glycolysis and its associated events represent the nutrient-sensitive restriction point in mammalian cells.
Slavica Tudzarova; Sergio L Colombo; Kai Stoeber; Saul Carcamo; Gareth H Williams; Salvador Moncada
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-03-14
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  108     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-30     Completed Date:  2011-06-10     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5278-83     Citation Subset:  IM    
Wolfson Institute for Biomedical Research and Research Department of Pathology, University College London, London WC1E 6BT, United Kingdom.
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MeSH Terms
Amino Acid Sequence
Cell Cycle / physiology*
Cell Proliferation
Enzyme Stability
Glucose / metabolism
Glycolysis / physiology*
HeLa Cells
Lactic Acid / metabolism
Molecular Sequence Data
Phosphofructokinase-2 / genetics,  metabolism*
RNA Interference
SKP Cullin F-Box Protein Ligases / metabolism*
Ubiquitin-Protein Ligase Complexes / metabolism*
Grant Support
086729//Wellcome Trust; C428/A6263//Cancer Research UK
Reg. No./Substance:
50-21-5/Lactic Acid; 50-99-7/Glucose; EC protein, human; EC; EC Cullin F-Box Protein Ligases; EC Ligase Complexes; EC complex

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