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PNAS 107 (16): 7461-7466

Copyright © 2010 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MEDICAL SCIENCES

Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species

Sawako Suzukia,b,1, Tomoaki Tanakaa,b,1, Masha V. Poyurovskyc, Hidekazu Naganoa,b, Takafumi Mayamaa,b, Shuichi Ohkubod, Maria Lokshinc, Hiroyuki Hosokawae, Toshinori Nakayamae, Yutaka Suzukif, Sumio Suganof, Eiichi Satog, Toshitaka Nagaog, Koutaro Yokotea,b, Ichiro Tatsunoa,b,2, and Carol Privesc,2

aDepartment of Clinical Cell Biology and bDivision of Endocrinology and Metabolism, Chiba University Graduate School of Medicine, Chiba-shi, Chiba 260-8670, Japan; cDepartment of Biological Sciences, Columbia University, New York, NY 10027; dDrug Discovery and Development I, Hanno Research Institute, Taiho Pharmaceutical Co., Ltd., Hanno, Saitama 357-8527, Japan; eDepartment of Immunology, Chiba University Graduate School of Medicine, Chiba-shi, Chiba 260-8670, Japan; fDepartment of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba 277-8562, Japan; and gDepartment of Anatomic Pathology, Tokyo Medical University, Shinjuku, Tokyo 160-0023, Japan

Contributed by Carol Prives, March 1, 2010 (sent for review January 6, 2010)

Abstract: We identified a p53 target gene, phosphate-activated mitochondrial glutaminase (GLS2), a key enzyme in conversion of glutamine to glutamate, and thereby a regulator of glutathione (GSH) synthesis and energy production. GLS2 expression is induced in response to DNA damage or oxidative stress in a p53-dependent manner, and p53 associates with the GLS2 promoter. Elevated GLS2 facilitates glutamine metabolism and lowers intracellular reactive oxygen species (ROS) levels, resulting in an overall decrease in DNA oxidation as determined by measurement of 8-OH-dG content in both normal and stressed cells. Further, siRNA down-regulation of either GLS2 or p53 compromises the GSH-dependent antioxidant system and increases intracellular ROS levels. High ROS levels following GLS2 knockdown also coincide with stimulation of p53-induced cell death. We propose that GLS2 control of intracellular ROS levels and the apoptotic response facilitates the ability of p53 to protect cells from accumulation of genomic damage and allows cells to survive after mild and repairable genotoxic stress. Indeed, overexpression of GLS2 reduces the growth of tumor cells and colony formation. Further, compared with normal tissue, GLS2 expression is reduced in liver tumors. Thus, our results provide evidence for a unique metabolic role for p53, linking glutamine metabolism, energy, and ROS homeostasis, which may contribute to p53 tumor suppressor function.

Key Words: glutathione antioxidant • glutaminolysis • tumor suppression • apoptosis

Author contributions: S. Suzuki, T.T., I.T., and C.P. designed research; S. Suzuki, T.T., H.N., T.M., S.O., M.L., H.H., T. Nakayama, Y.S., S. Sugano, E.S., T. Nagao, and K.Y. performed research; H.N., T.M., E.S., and T. Nagao contributed new reagents/analytic tools; T.T., M.V.P., S.O., M.L., Y.S., S. Sugano, K.Y., and C.P. analyzed data; and S. Suzuki, T.T., M.V.P., I.T., and C.P. wrote the paper.

1S. Suzuki and T. Tanaka contributed equally to this work.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/1002459107/DCSupplemental.

See Commentary on page 7117.

2To whom correspondence may be addressed. E-mail: ichiro-tatsuno{at}faculty.chiba-u.jp or clp3{at}columbia.edu.

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