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PNAS 107 (16): 7455-7460

Copyright © 2010 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function

Wenwei Hua, Cen Zhanga, Rui Wua, Yvonne Suna, Arnold Levinea,b,1, and Zhaohui Fenga,1

aCancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903; and b Institute for Advanced Study, Princeton, NJ 08540

Contributed by Arnold J. Levine, January 28, 2010 (sent for review November 30, 2009)

Abstract: Whereas cell cycle arrest, apoptosis, and senescence are traditionally thought of as the major functions of the tumor suppressor p53, recent studies revealed two unique functions for this protein: p53 regulates cellular energy metabolism and antioxidant defense mechanisms. Here, we identify glutaminase 2 (GLS2) as a previously uncharacterized p53 target gene to mediate these two functions of the p53 protein. GLS2 encodes a mitochondrial glutaminase catalyzing the hydrolysis of glutamine to glutamate. p53 increases the GLS2 expression under both nonstressed and stressed conditions. GLS2 regulates cellular energy metabolism by increasing production of glutamate and {alpha}-ketoglutarate, which in turn results in enhanced mitochondrial respiration and ATP generation. Furthermore, GLS2 regulates antioxidant defense function in cells by increasing reduced glutathione (GSH) levels and decreasing ROS levels, which in turn protects cells from oxidative stress (e.g., H2O2)-induced apoptosis. Consistent with these functions of GLS2, the activation of p53 increases the levels of glutamate and {alpha}-ketoglutarate, mitochondrial respiration rate, and GSH levels and decreases reactive oxygen species (ROS) levels in cells. Furthermore, GLS2 expression is lost or greatly decreased in hepatocellular carcinomas and the overexpression of GLS2 greatly reduced tumor cell colony formation. These results demonstrated that as a unique p53 target gene, GLS2 is a mediator of p53’s role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression.

Key Words: reactive oxygen species • oxidative phosphorylation

Author contributions: W.H., A.L., and Z.F. designed research; W.H., C.Z., R.W., Y.S., and Z.F. performed research; W.H., A.L., and Z.F. analyzed data; and W.H., A.L., and Z.F. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/1001006107/DCSupplemental.

See Commentary on page 7117.

1To whom correspondence may be addressed. E-mail: alevine{at}ias.edu or fengzh{at}umdnj.edu.

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