G0S2

Official Full Name

G0/G1 switch 2

Organism

Homo sapiens

GeneID

50486

Background

Involved in extrinsic apoptotic signaling pathway and positive regulation of extrinsic apoptotic signaling pathway. Located in mitochondrion. [provided by Alliance of Genome Resources, Feb 2025]

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Detailed Information

The G0/G1 switch gene 2 (G0S2) was discovered by Russell and Forsdyke in cultured mononuclear cells during the drug-induced cell cycle transition from G0 to G1 phase. G0S2 exists in vertebrates and has no homologs in lower organisms such as Drosophila and Caenorhabditis elegans. In both human and mouse, G0S2 is located on chromosome 1 of the genome and encodes a small basic protein of 103 amino acids. G0S2 protein is highly conserved between species; there is 78% identity between human and mouse isoforms. According to protein secondary structure prediction, the G0S2 protein comprises two α-helices separated by a hydrophobic sequence with the possible to generate turns and assume a β-sheet conformation. Moreover, there are several putative phosphorylation sites for protein kinase C (PKC) and casein kinase II within the sequence of G0S2, while no evidence has been obtained that G0S2 is actually a phosphoprotein.

The expression of G0S2 has been profiled in various human and mouse cell types. As with a number of highly regulated and conserved genes present throughout the genome, G0S2 features a CpG-rich island that potentially allows for germ-line expression. Results from a limited number of studies have implied that G0S2 is a multifaceted protein involved in proliferation, apoptosis, metabolism, inflammation, and carcinogenesis. In particular, recent studies have provided compelling evidence that G0S2 is abundantly expressed in metabolically active tissues such as liver and fat, and acts as a molecular brake on triglyceride (TG) catabolism.

Physiologic role of G0S2 in regulating lipid and energy metabolism

In the fed state, G0S2 protein expression increases in adipose tissue and decreases in the liver; these changes are reversed by subsequent fasting. The generation and phenotypic characterization of multiple G0S2 overexpression and knockout animal models have shed light on the physiologic function of G0S2 in tissue-specific lipolysis and global energy homeostasis. Generally, the findings obtained from different studies have been remarkably consistent in showing in different tissue settings that G0S2 inhibits lipolysis by direct protein-protein interaction with adipose triglyceride lipase (ATGL) (Figure 1).

G0S2 Figure 1. ATGL-dependent and independent functions of G0S2.

In three G0S2 whole-body knockout mouse models, basal as well as stimulated lipolytic rates were increased in the white adipose tissue (WAT). As a result, these mice were lean, cold tolerant and resistant to HFD-induced obesity and insulin resistance. The increased energy expenditure observed in these mice was explained by augmented adipocyte fatty acid (FA) oxidation, which promoted thermogenic function of BAT and browning-like changes in WAT. On the contrary, transgenic overexpression of G0S2 in mice strongly attenuated adipose lipolysis and FA flux to liver in response to fasting and β-adrenergic stimulation. Consequently, these mice experienced difficulty in shifting from carbohydrate to FA oxidation during fasting. Moreover, G0S2 overexpression promoted accumulation of more and larger lipid droplets (LDs) in brown adipocytes, leading to defective cold adaptation in the transgenic mice. In response to HFD feeding, the transgenic mice displayed a greater gain in body weight and adiposity along with decreases in the fasting plasma levels of free FAs, insulin and TG. Together, these studies have demonstrated an important role for G0S2 as a regulator of adipose lipolysis and the overall FA availability.

G0S2 in cancer development

Some studies have linked the epigenetic regulation of G0S2 expression to carcinogenesis. The G0S2 gene was reported to be hypermethylated in some human cancer cell lines as well as in squamous head, neck and lung cancers. A causal relationship between DNA methylation and suppression of G0S2 expression was established by the treatment of LC-1/sq squamous lung cancer cells with DNA demethylating agent 5-Aza-2′-deoxycytidine. In addition, G0S2 was found to localize different subcellular membrane structures including endoplasmic reticulum (ER) and mitochondria. A study also showed that G0S2 interacts with Bcl-2 at the mitochondria and thereby modulates its anti-apoptotic activity in human cancer cells.

Moreover, the G0S2 was also found to be a target of all-trans retinoic acid (RA) in human acute promyelocytic leukemia (APL) cells. RA treatment is a model of effective therapy based on inducing terminal differentiation of APL cells. Both mRNA and protein of G0S2 were rapidly induced in cultured human APL cells and in APL transgenic mice treated with RA. In addition, the G0S2 promoter contains RA response element (RARE) half-sites, and mutations within RARE blocked all RA induced transcriptional activation. Although the evidence supporting G0S2's ability to act as an RA target gene is convincing, the functional role of G0S2 in the RA response of APL remains undefined.

References:

Zhang X, et al. G0S2: A small giant controller of lipolysis and adipose-liver fatty acid flux. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2017, 1862(10 Pt B).
Yim C Y, et al. G0S2 suppresses oncogenic transformation by repressing a Myc-regulated transcriptional program. Cancer Research, 2016, 76(5):1204.
Tian M A, et al. Repression of exogenous gene expression by the retinoic acid target gene G0S2. International Journal of Oncology, 2013, 42(5):1743.
Heckmann B L, et al. The G0/G1 Switch Gene 2 (G0S2): Regulating metabolism and beyond. Biochimica Et Biophysica Acta, 2013, 1831(2):276.
Heier C, Zimmermann R. The sparing use of fat: G0s2, controls lipolysis and fatty acid oxidation. Diabetologia, 2015, 58(1):7-9.

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