Ribosome binding protein GCN1 regulates the cell cycle and cell proliferation and is essential for the embryonic development of mice

Abstract

Amino acids exert many biological functions, serving as allosteric regulators and neurotransmitters, as constituents in proteins and as nutrients. GCN2-mediated phosphorylation of eukaryotic initiation factor 2 alpha (elF2α) restores homeostasis in response to amino acid starvation (AAS) through the inhibition of the general translation and upregulation of amino acid biosynthetic enzymes and transporters by activating the translation of Gcn4 and ATF4 in yeast and mammals, respectively. GCN1 is a GCN2-binding protein that possesses an RWD binding domain (RWDBD) in its C-terminus. In yeast, Gcn1 is essential for Gcn2 activation by AAS; however, the roles of GCN1 in mammals need to be established. Here, we revealed a novel role of GCN1 that does not depend on AAS by generating two Gcn1 mutant mouse lines: Gcn1-knockout mice (Gcn1 KO mice (Gcn1-/-)) and RWDBD-deleted mutant mice (Gcn1 ΔRWDBD mice). Both mutant mice showed growth retardation, which was not observed in the Gcn2 KO mice, such that the Gcn1 KO mice died at the intermediate stage of embryonic development because of severe growth retardation, while the Gcn1 ΔRWDBD embryos showed mild growth retardation and died soon after birth, most likely due to respiratory failure. Extension of pregnancy by 24 h through the administration of progesterone to the pregnant mothers rescued the expression of differentiation markers in the lungs and prevented lethality of the Gcn1 ΔRWDBD pups, indicating that perinatal lethality of the Gcn1 ΔRWDBD embryos was due to simple growth retardation. Similar to the yeast Gcn2/ Gcn1 system, AAS-or UV irradiation-induced elF2α phosphorylation was diminished in the Gcn1 ΔRWDBD mouse embryonic fibroblasts (MEFs), suggesting that GCN1 RWDBD is responsible for GCN2 activity. In addition, we found reduced cell proliferation and G2/M arrest accompanying a decrease in Cdk1 and Cyclin B1 in the Gcn1 ΔRWDBD MEFs. Our

MIRO2 Regulates Prostate Cancer Cell Growth via GCN1-Dependent Stress Signaling

“…GCN1 is the upstream activator of GCN2/EIF2AK4, a serine/threonine kinase that senses amino acid availability, redox status and actin dynamics cues in cells (29,30). A recent study linked GCN1 to cell cycle regulation and proliferation in developing mice (31). However, there is no evidence of GCN1's importance for cancer cells.…”

Genome-wide association study using haplotype libraries and repeated-measures model to identify candidate genomic regions for stillbirth in Holstein cattle

“…The QTL enrichment analysis indicated a total of 45 enriched QTL (Supplemental Table S8, https: / / data .mendeley .com/ datasets/ nnp5hdy9cv/ 1; Fonesca et al, 2021), from which 13 were reproduction-related QTL (Figure 4). The BTA5 and BTA14 were those with the largest number of reproduction-related QTL identified as Zhang et al, 2002;Yamazaki et al, 2020 enriched (5 and 3, respectively; Table 2). Additionally, the relationship between the enriched fertility-related QTL, the haplotypes significantly associated with stillbirth, and the genes mapped within the haplotypes is shown in the Figure 5.…”

Valproic Acid: A Promising Therapeutic Agent in Glioma Treatment

“…Cell proliferation, one of the important physiological functions of tumor cells, is the basis of growth, development, reproduction, and heredity (43). Moreover, cellular migration and invasion are also the most important features of malignant tumors, mainly involved in cancer metastasis (44).…”