p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase : Nature Cell Biology : Nature Publishing Group

p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase

Peng Jiang,1, 2 Wenjing Du,1, 2 Xingwu Wang,1 Anthony Mancuso,2 Xiang Gao,3 Mian Wu1 & Xiaolu Yang2

Journal name: Nature Cell Biology
Year published:(2011)
DOI: doi:10.1038/ncb2172
Received08 November 2010
Accepted25 November 2010
Published online20 February 2011




Cancer cells consume large quantities of glucose and primarily use glycolysis for ATP production, even in the presence of adequate oxygen1, 2. This metabolic signature (aerobic glycolysis or the Warburg effect) enables cancer cells to direct glucose to biosynthesis, supporting their rapid growth and proliferation3, 4. However, both causes of the Warburg effect and its connection to biosynthesis are not well understood. Here we show that the tumour suppressor p53, the most frequently mutated gene in human tumours, inhibits the pentose phosphate pathway5 (PPP). Through the PPP, p53 suppresses glucose consumption, NADPH production and biosynthesis. The p53 protein binds to glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting enzyme of the PPP, and prevents the formation of the active dimer. Tumour-associated p53 mutants lack the G6PD-inhibitory activity. Therefore, enhanced PPP glucose flux due to p53 inactivation may increase glucose consumption and direct glucose towards biosynthesis in tumour cells.

Figures at a glance
leftFigure 1: p53 deficiency correlates with increases in PPP flux, glucose consumption and lactate production.
(a) p53+/+ and p53−/− HCT116 cells were cultured in medium containing [2-13C]glucose. Oxidative PPP flux (top) was measured based on the rate of glucose consumption and the ratio of 13C incorporated into carbon 2 (indicating glycolysis) and carbon 3 (indicating PPP) of lactate by NMR spectroscopy. Data are means ± s.d. (n=3). Protein expression is shown at the bottom, with molecular weight standards indicated on the left. (b) p53+/+ and p53−/− HCT116 cells were treated with G6PD siRNA and control siRNA (−). Top: glucose consumption. Data are means ± s.d. (n=3). Bottom: the expression of p53, G6PD and actin (a loading control). (c) p53+/+ and p53−/− MEF cells were treated with 1 mM DHEA or vehicle (−) for 24 h. Top: glucose consumption. Data are means ± s.d. (n=3). Bottom: protein expression (d,e). Lactate levels in cells from b (d) and c (e). Data are means ± s.d. (n=3 for each panel).
Figure 2: p53 regulates NADPH levels, lipid accumulation and G6PD activity.


These authors contributed equally to this work
Peng Jiang & Wenjing Du

Affiliations
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230027, China
Peng Jiang,Wenjing Du,Xingwu Wang &Mian Wu
Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19096, USA
Peng Jiang,Wenjing Du,Anthony Mancuso &Xiaolu Yang
Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
Xiang Gao

Contributions
P.J., W.D., M.W. and X.Y. designed the experiments and interpreted results. P.J. and W.D. carried out all the experiments, except those mentioned below. X.W. carried out the experiments on G6PD activity in yeast, the surface plasmon resonance, and lipid droplets in mouse liver. A.M. and P.J. analysed the oxidative PPP flux. X.G. supplied the p53 wild-type and knockout mice. X.Y. wrote the manuscript with the help of P.J. and W.D.

Competing financial interests
The authors declare no competing financial interests.

p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase : Nature Cell Biology : Nature Publishing Group




ONCOLOGÍA
Actualidad Ultimas noticias - JANOes y agencias -
La ausencia de la proteína p53 fomenta la proliferación de las células cancerosas
JANO.es y agencias · 21 Febrero 2011 12:59

Científicos estadounidenses publican que las células que carecen de p53 funcional consumen grandes cantidades de glucosa a través del mecanismo ox-PPP.


La pérdida de la proteína supresora tumoral p53 podría subyacer a la capacidad de las células cancerosas a pasar por un cambio metabólico que apoya su proliferación rápida para afrontar la disponibilidad limitada de nutrientes, según un estudio de la Universidad de Pennsylvania (Estados Unidos).

El descubrimiento, que se publica en la edición digital de Nature Cell Biology, refuerza la importancia de la pérdida de p53 en el desarrollo del cáncer.
Esta proteína es conocida por modular el metabolismo de las células del cáncer al regular la transcripción genética dentro del núcleo.

Los investigadores descubrieron que las células que carecían de p53 funcional consumían grandes cantidades de glucosa a través del mecanismo ox-PPP, que apoya la biosíntesis de nuevos bloques de construcción celular a partir de glucosa y es crítico para la proliferación de las células del cáncer.

Los autores descubrieron que p53 interactúa con una enzima clave en el mecanismo ox-PPP fuera del núcleo. Los investigadores concluyen que p53 normalmente inhibe esta enzima para bloquear el mecanismo ox-PPP pero que la pérdida de p53 elimina este bloqueo y activa el mecanismo.

Nature Cell Biology 2011; doi:10.1038/ncb2172
p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase : Nature Cell Biology : Nature Publishing Group

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