Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function.
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., H(2)O(2))-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.
Hu
Wenwei
W
Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
Zhang
Cen
C
Wu
Rui
R
Sun
Yvonne
Y
Levine
Arnold
A
Feng
Zhaohui
Z
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007656:Ketoglutaric Acids / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species; D000637:Transaminases / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000975:Antioxidants; D007656:Ketoglutaric Acids; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D000637:Transaminases; C020656:glutamine-pyruvate aminotransferase; D005978:Glutathione; D010100:Oxygen