Gls-KO Mouse

Gls, also known as glutaminase, is an enzyme that converts glutamine into glutamate [2]. Glutamate is the most abundant central nervous system neurotransmitter, and thus Gls plays a crucial role in maintaining glutamate homeostasis [2,6]. The enzyme is involved in various biological processes, and its activity is closely related to metabolism, cell growth, and development [1,3]. Altered glutamine metabolism, with Gls as a key regulator, has been linked to the development of many diseases [3].

In cancer research, Gls shows promise as a biomarker and potential therapeutic target. In breast cancer, it is aberrantly over-expressed, has a high ROC-AUC value for diagnosis, and is related to tumor growth, metastasis, and the immune tumor microenvironment [1]. In prostate cancer, Gls is up-regulated, and its knockdown suppresses cell proliferation, promotes apoptosis, and arrests the cell cycle, also suppressing the Wnt/β-catenin pathway [3]. In lung cancer, certain Gls gene polymorphisms are associated with reduced susceptibility [5]. In acute myocardial infarction, Gls has good diagnostic value and is associated with immune-and hypoxia-related pathways [4]. Loss-of-function mutations in Gls can cause autosomal recessive spastic ataxia and optic atrophy [6], while a gain-of-function variant leads to glutamate excess, infantile cataract, and profound developmental delay [2].

In conclusion, Gls is essential for maintaining glutamate homeostasis and is involved in multiple biological processes. Its dysregulation is associated with various diseases, including cancer, neurodegenerative disorders, and metabolic diseases. Functional studies, especially those using loss-of-function models, have provided valuable insights into its role in disease development, highlighting its potential as a diagnostic biomarker and therapeutic target.

References:

1. Zhang, Danfeng, Wang, Man, Huang, Xufeng, Li, Zhengrui, Wang, Geng. 2023. GLS as a diagnostic biomarker in breast cancer: in-silico, in-situ, and in-vitro insights. In Frontiers in oncology, 13, 1220038. doi:10.3389/fonc.2023.1220038. https://pubmed.ncbi.nlm.nih.gov/37664031/

2. Rumping, Lynne, Tessadori, Federico, Pouwels, Petra J W, Jans, Judith J M, van Hasselt, Peter M. . GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay. In Human molecular genetics, 28, 96-104. doi:10.1093/hmg/ddy330. https://pubmed.ncbi.nlm.nih.gov/30239721/

3. Zhang, Junfeng, Mao, Shiyu, Guo, Yadong, Yao, Xudong, Huang, Yong. 2019. Inhibition of GLS suppresses proliferation and promotes apoptosis in prostate cancer. In Bioscience reports, 39, . doi:10.1042/BSR20181826. https://pubmed.ncbi.nlm.nih.gov/31196962/

4. Liu, Zheng, Wang, Lei, Xing, Qichang, Liu, Renzhu, Huang, Nan. 2022. Identification of GLS as a cuproptosis-related diagnosis gene in acute myocardial infarction. In Frontiers in cardiovascular medicine, 9, 1016081. doi:10.3389/fcvm.2022.1016081. https://pubmed.ncbi.nlm.nih.gov/36440046/

5. Wang, Yuhe, Chen, Mingyue, Yi, Faling, Jin, Tianbo, Chen, Mingwei. . Association between GLS Gene Polymorphisms and the Susceptibility to Lung Cancer in the Chinese Han Population. In Frontiers in bioscience (Landmark edition), 28, 95. doi:10.31083/j.fbl2805095. https://pubmed.ncbi.nlm.nih.gov/37258469/

6. Lynch, David S, Chelban, Viorica, Vandrovcova, Jana, Wood, Nicholas W, Houlden, Henry. 2018. GLS loss of function causes autosomal recessive spastic ataxia and optic atrophy. In Annals of clinical and translational neurology, 5, 216-221. doi:10.1002/acn3.522. https://pubmed.ncbi.nlm.nih.gov/29468182/