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Identification of TP53-induced glycolysis and apoptosis regulator (TIGAR) as the phosphoglycolate-independent 2,3-bisphosphoglycerate phosphatase.

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Gerin, Isabelle [UCL] Noël, Gaetane [UCL] Bolsée, Jennifer Haumont, Olivier Van Schaftingen, Emile [UCL] Bommer, Guido [UCL]

The p53-induced protein TIGAR is considered to be a fructose-2,6-bisphosphatase (F26BPase) with an important role in cancer cell metabolism. The reported catalytic efficiency of TIGAR as F26BPase is several orders of magnitude lower than that of the F26BPase component of liver or muscle PFK2-F26BPase, suggesting that fructose 2,6-bisphosphate (F26BP) might not represent the physiologic substrate of TIGAR. We therefore set out to re-evaluate the biochemical function of TIGAR. Phosphatase activity of recombinant human TIGAR protein was tested on a series of physiological phosphate esters. The best substrate was 2,3-bisphosphoglycerate (23BPG), followed by 2-phosphoglycerate (2PG) and phosphoenolpyruvate (PEP). In contrast the catalytic efficiency for F26BP was about 400-fold lower than that for 23BPG. Using genetic and shRNA-based cell culture models, we show that loss of TIGAR consistently leads up to a five-fold increase in 23BPG levels. Increases in F26BP levels were also observed, albeit in a more limited and cell-type dependent manner. Our data challenge the concept that TIGAR primarily acts on fructose 2,6-bisphosphate. This has significant implications for our understanding of the metabolic changes downstream of p53 as well as for cancer cell metabolism in general. It also suggests that 23BPG might play an unrecognized function in metabolic control.

Document type Article de périodique (Journal article)
Access type Accès interdit
Publication date 2014
Language Anglais
Journal information "Biochemical Journal" - Vol. 458, no. 3, p. 439-448 (2014)
Peer reviewed yes
Publisher Portland Press Ltd. ((United Kingdom) London)
issn 0264-6021
e-issn 1470-8728
Publication status Publié
Affiliation UCL - SSS/DDUV - Institut de Duve
Keywords 23-bisphosphoglycerate ; fructose-2 ; 6-bisphosphatase ; glycolysis ; glycolytic shunt ; p53 ; TP53
Links
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Bibliographic reference Gerin, Isabelle ; Noël, Gaetane ; Bolsée, Jennifer ; Haumont, Olivier ; Van Schaftingen, Emile ; et. al. Identification of TP53-induced glycolysis and apoptosis regulator (TIGAR) as the phosphoglycolate-independent 2,3-bisphosphoglycerate phosphatase.. In: Biochemical Journal, Vol. 458, no. 3, p. 439-448 (2014)
Permanent URL http://hdl.handle.net/2078.1/139949