Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 44, Pages 18868-18873Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1012362107
Keywords
cell cycle; glutaminase; 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3; proliferation
Categories
Funding
- Wellcome Trust [086729]
- Pharmaceutical Biotechnology Centre of the University of Rome Tor Vergata
- Fonds zur Forderung der wissenschaftlichen Forschung [J2957-B11]
- UK Biotechnology and Biological Sciences Research Council [36801]
- Innovate UK [36801] Funding Source: UKRI
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Cell proliferation is accompanied by an increase in the utilization of glucose and glutamine. The proliferative response is dependent on a decrease in the activity of the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)-Cdh1 which controls G1-to- S-phase transition by targeting degradation motifs, notably the KEN box. This occurs not only in cell cycle proteins but also in the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatase isoform 3 (PFKFB3), as we have recently demonstrated in cells in culture. We now show that APC/C-Cdh1 controls the proliferative response of human T lymphocytes. Moreover, we have found that glutaminase 1 is a substrate for this ubiquitin ligase and appears at the same time as PFKFB3 in proliferating T lymphocytes. Glutaminase 1 is the first enzyme in glutaminolysis, which converts glutamine to lactate, yielding intermediates for cell proliferation. Thus APC/C-Cdh1 is responsible for the provision not only of glucose but also of glutamine and, as such, accounts for the critical step that links the cell cycle with the metabolic substrates essential for its progression.
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