The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a sensor of different environmental conditions and regulator of cell growth, metabolism and autophagy. mTORC1 is activated by Rag GTPases, working as RagA:B and RagC:D heterodimers. Rags control mTORC1 activity by tethering mTORC1 to the lysosomes where it is activated by Rheb GTPase. RagA:B, active in its GTP-bound form, is inhibited by GATOR1 complex, a GTPase activating protein (GAP) and GATOR1 in turn is negatively regulated by GATOR2 complex. Sestrins are stress-responsive proteins that inhibit mTORC1 via activation of AMP-activated protein kinase (AMPK) and tuberous sclerosis complex. Here we report an AMPK-independent mechanism of mTORC1 inhibition by Sestrins mediated by their interaction with GATOR2. As a result of this interaction the Sestrins suppress lysosomal mTOR localization in a Rag-dependent manner. This mechanism is potentially involved in mTORC1 regulation by amino acids, rotenone and tunicamycin, connecting stress response with mTORC1 inhibition.

The purpose of our study was to examine the roles of green tea drinking, other risk and protective factors, and polymorphism of susceptibility genes such as GSTM1, GSTT1, GSTP1, and p53 codon 72 and their possible joint effects on the risk of stomach cancer. A population-based case-control study was conducted in Taixing, China, including 206 newly diagnosed cases with stomach cancer and 415 healthy control subjects. Epidemiological data were collected by in-person interviews using a standard questionnaire. Polymorphisms of susceptibility genes were assayed by PCR-RFLP techniques. A multigenetic index was created by summing up the number of risk genotypes. The data were analyzed using the logistic regression model. A reverse association between green tea drinking and risk of stomach cancer was observed with an adjusted odds ratio (OR) of 0.59 (95% confidence interval [CI] 5 0.34-1.01). Dose-response relationship was shown (p-trend < 0.05). A higher score on the multigenetic index was associated with increased risk of stomach cancer with an adjusted OR of 2.21 (95% CI 5 1.02-4.79) for those with at least 3 risk genotypes compared to those with <2 risk genotypes. Green tea drinking was suggested to have more than multiplicative interactions with alcohol consumption with an adjusted OR for interaction of 4.57 (95% CI 5 1.62-12.89), and with higher multigenetic index with adjusted OR for interaction of 2.31 (95% CI 5 0.88-6.03). The protective effect of green tea drinking was observed on the risk of stomach cancer and the possible effect modification by susceptibility genes was suggested. ' 2005 Wiley-Liss, Inc.

Sestrin2 is a member of a family of stress responsive proteins, which controls cell viability via antioxidant activity and regulation of the mammalian target of rapamycin protein kinase (mTOR). Sestrin2 is induced by different stress insults, which diminish ATP production and induce energetic stress in the cells. Glucose is a critical substrate for ATP production utilized via glycolysis and mitochondrial respiration as well as for glycosylation of newly synthesized proteins in the endoplasmic reticulum (ER) and Golgi. Thus, glucose starvation causes both energy deficiency and activation of ER stress followed by the unfolding protein response (UPR). Here, we show that UPR induces Sestrin2 via ATF4 and NRF2 transcription factors and demonstrate that Sestrin2 protects cells from glucose starvation-induced cell death. Sestrin2 inactivation sensitizes cells to necroptotic cell death that is associated with a decline in ATP levels and can be suppressed by Necrostatin 7. We propose that Sestrin2 protects cells from glucose starvation-induced cell death via regulation of mitochondrial homeostasis.

Coal Workers’ Pneumoconiosis (CWP) is the primary occupational disease in China. However, information about the definite prevalence of CWP is only partially available. The aims of our study were to assess the prevalence characteristics of CWP in a state-owned coal mine, evaluate the effects of control measures and develop further preventive strategies for CWP. The total study population included 495 cases who were diagnosed with CWP from the construction of this coal mine to the end of October 2014. Individuals’ information, including duration of dust exposure, job titles, age as first diagnosis, stages of CWP, CWP progress, complications with pulmonary tuberculosis, death and others were collected and analyzed. The results showed that 71.11% of 495 CWP cases were stage I and 90.71% were involved in tunneling or coal mining. The mean dust exposure period in CWP patients was 26.7 years, the mean latent period was 29.3 years and the mean diagnosed age was 50.3 years old. The proportion of CWP diagnosed after ending dust exposure were remarkably increased with the time passing. Among the CWP cases, 36 (7.27%) were complicated with pulmonary tuberculosis. The mortality of patients with stage III was the highest (60.71%) (p < 0.0001). Our data obviously show that more strict policies to protect coal miners are needed to be implemented in China, especially for tunneling and mining workers.

The incidence of stomach cancer is high in certain parts of the world, particularly in China. Chronic Helicobacter pylori infection is the main risk factor, yet the vast majority of infected individuals remain unaffected with cancer, suggesting an important role of other risk factors. We conducted a population-based case-control study including 196 incident stomach cancer cases and 397 matched controls to test the hypothesis that adverse single nucleotide polymorphism (SNP) genotypes and haplotypes within genes of the DNA repair and immune regulatory pathways are associated with increased stomach cancer risk. Genomic DNA isolated from blood samples was used for genotyping, and results were obtained for 57 putatively functional SNPs in 28 genes. Odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from adjusted logistic regression models. For PTGS2, a gene involved in the inflammatory response, associations with stomach cancer risk were observed for TC genotype carriers of rs5279 (OR, 0.24; 95% CI, 0.08-0.73), CT genotype carriers of the 3′-untranslated region SNP rs689470 (OR, 7.49; 95% CI, 1.21-46.20), and CTTC haplotype carriers of rs5277, rs5278, rs5279, and rs689470 (OR, 0.41; 95% CI, 0.18-0.95). For ERCC5, a gene involved in nucleotide excision repair, TC genotype carriers of rs1047768 (OR, 0.65; 95% CI, 0.41-1.03), GC genotype carriers of the nonsynonymous SNP rs2227869 (OR, 0.30; 95% CI, 0.13-0.67), and CCG haplotype carriers of rs1047768, rs17655, and rs2227869 (OR, 0.45; 95% CI, 0.20-1.04) were associated with reduced stomach cancer risk. In conclusion, PTGS2 and ERCC5 were associated with stomach cancer risk in a