Document Detail

Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells.
MedLine Citation:
PMID:  22106309     Owner:  NLM     Status:  MEDLINE    
During cell division, the activation of glycolysis is tightly regulated by the action of two ubiquitin ligases, anaphase-promoting complex/cyclosome-Cdh1 (APC/C-Cdh1) and SKP1/CUL-1/F-box protein-β-transducin repeat-containing protein (SCF-β-TrCP), which control the transient appearance and metabolic activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, isoform 3 (PFKFB3). We now demonstrate that the breakdown of PFKFB3 during S phase occurs specifically via a distinct residue (S(273)) within the conserved recognition site for SCF-β-TrCP. Glutaminase 1 (GLS1), the first enzyme in glutaminolysis, is also targeted for destruction by APC/C-Cdh1 and, like PFKFB3, accumulates after the activity of this ubiquitin ligase decreases in mid-to-late G1. However, our results show that GLS1 differs from PFKFB3 in that its recognition by APC/C-Cdh1 requires the presence of both a Lys-Glu-Asn box (KEN box) and a destruction box (D box) rather than a KEN box alone. Furthermore, GLS1 is not a substrate for SCF-β-TrCP and is not degraded until cells progress from S to G2/M. The presence of PFKFB3 and GLS1 coincides with increases in generation of lactate and in utilization of glutamine, respectively. The contrasting posttranslational regulation of PFKFB3 and GLS1, which we have verified by studies of ubiquitination and protein stability, suggests the different roles of glucose and glutamine at distinct stages in the cell cycle. Indeed, experiments in which synchronized cells were deprived of either of these substrates show that both glucose and glutamine are required for progression through the restriction point in mid-to-late G1, whereas glutamine is the only substrate essential for the progression through S phase into cell division.
Sergio L Colombo; Miriam Palacios-Callender; Nanci Frakich; Saul Carcamo; Istvan Kovacs; Slavica Tudzarova; Salvador Moncada
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-11-21
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 Dec 
Date Detail:
Created Date:  2011-12-28     Completed Date:  2012-02-21     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21069-74     Citation Subset:  IM    
Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom.
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MeSH Terms
Cell Division / physiology*
DNA Primers / genetics
Flow Cytometry
Glucose / metabolism
Glutaminase / metabolism*
Glutamine / metabolism
Glycolysis / physiology*
HeLa Cells
Phosphofructokinase-2 / metabolism*
Plasmids / genetics
Protein Processing, Post-Translational / physiology*
SKP Cullin F-Box Protein Ligases / metabolism*
Ubiquitin-Protein Ligase Complexes / metabolism*
Grant Support
086729//Wellcome Trust
Reg. No./Substance:
0/DNA Primers; 50-99-7/Glucose; 56-85-9/Glutamine; EC protein, human; EC; EC; EC Cullin F-Box Protein Ligases; EC Ligase Complexes; EC complex
Comment In:
Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):20857-8   [PMID:  22173637 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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