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.