Medical Research Council; Toxicology Unit; Leicester University; Leicester, UK; Institute of Health Sciences; Shanghai Institutes for Biological Sciences; Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; Shanghai, China.
Cell Cycle. 2013 Nov 15;12(22):3564-73. doi: 10.4161/cc.26771. Epub 2013 Oct 10.
The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis.
氨基酸谷氨酰胺通过脱酰胺反应转化为谷氨酸，该反应由酶谷氨酰胺酶（GLS）催化。该酶已描述了两种同工酶，而 GLS2 同工酶受肿瘤抑制基因 p53 的调节。在这里，我们表明 p53 家族成员 TAp73 也可驱动 GLS2 的表达。具体来说，我们证明 TAp73 在维甲酸诱导的神经母细胞瘤细胞终末神经元分化过程中调节 GLS2 的表达，并且 GLS2 的过表达或抑制可调节神经元分化和细胞内 ATP 水平。此外，通过从生长培养基中去除谷氨酰胺来抑制 GLS 活性会损害皮质神经元的体外分化。最后，在小鼠小脑发育过程中，GLS2 的表达增加。尽管 p73 在 GLS2 的体内表达中不是必需的，但 TAp73 的缺失会影响皮质神经元中 GABA 和谷氨酸的水平。总之，这些发现表明 GLS2 在神经元分化中至少部分地作为 p73 的下游发挥作用，并强调了 p73 在调节神经递质合成中的可能作用。
