Expression of the HER2 oncogene is increased in ϳ30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase ␣ (ACC␣) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACC␣ compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACC␣ in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACC␣, and the HER2-mediated increase in ACC␣ and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACC␣. On the other hand, FASN and ACC␣ were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5-and 3-untranslated regions of both FASN and ACC␣ mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACC␣ in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.Because OA-519, a poor prognostic marker found in breast cancer cells, was shown to be a fatty acid synthase (FASN) 3 (1),a number of studies have demonstrated abnormally high levels of FASN in many human epithelial cancers and preneoplastic lesions (2, 3). FASN, a lipogenic enzyme, catalyzes the biosynthesis of palmitic acid that is used for the synthesis of triacylglycerol as a storage fuel molecule as well as membrane lipids including phospholipids and sphingolipids (4). In breast cancer cells, the expression of FASN is closely related to the aggressiveness of cancers as well as to the development, maintenance, and cell cycle progression of human cancers (5-7). Breast cancer cells that overexpress FASN undergo apoptosis when treated with small interfering RNAs (siRNAs) against FASN or FASN inhibitors, such as C75 and cerulenin (8 -11). Under physiological conditions, the activities of lipogenic enzymes, including FASN, are tightly regulated by nutritional and hormonal parameters at the transcription level. Sterol regulatory element-binding proteins (SREBP-1a, SREBP-1c, and SREBP-2) are the major transcription factors that mediate this regulation (12). SREBPs reside in endoplasmic reticulum membranes as inactive precursors. To become active, the NH 2 -terminal segments of SREBPs are released from the endoplasmic reticulum by proteolytic cleavage and enter the nucleus where they activate their target genes. SREBP-1 preferentially activates the genes in...

The carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper transcription factor, plays a critical role in the control of lipogenesis in the liver. To identify the direct targets of ChREBP on a genome-wide scale and provide more insight into the mechanism by which ChREBP regulates glucose-responsive gene expression, we performed chromatin immunoprecipitation-sequencing and gene expression analysis. We identified 1153 ChREBP binding sites and 783 target genes using the chromatin from HepG2, a human hepatocellular carcinoma cell line. A motif search revealed a refined consensus sequence (CABGTG-nnCnG-nGnSTG) to better represent critical elements of a functional ChREBP binding sequence. Gene ontology analysis shows that ChREBP target genes are particularly associated with lipid, fatty acid and steroid metabolism. In addition, other functional gene clusters related to transport, development and cell motility are significantly enriched. Gene set enrichment analysis reveals that ChREBP target genes are highly correlated with genes regulated by high glucose, providing a functional relevance to the genome-wide binding study. Furthermore, we have demonstrated that ChREBP may function as a transcriptional repressor as well as an activator.

To determine the actual firefighter injury statistics in Korea, we conducted a survey on the nature of on-duty injuries among all male firefighters in Korea. We distributed questionnaires to all Korean male firefighters via email, and data from the 19,119 workers that responded were used for data analysis. The job types were categorized into fire suppression, emergency medical service (EMS) and officers. As estimated of age standardized injury prevalence per one thousand workers, 354 fire extinguishing personnel, 533 EMS workers, and 228 officers experienced one or more injuries during the previous 12 months. The odds ratio (95% confidence interval) of injuries was 1.86 (1.61–2.15) for fire suppression and 2.93 (2.51–3.42) for EMS personnel compared to officers after adjusting for age, marital status, smoking habit and career period. Age standardized absence days from work due to injuries per one thousand workers were 1,120, 1,337, and 676 for fire suppression, EMS and officers, respectively. Car accident (24.5%) was the most common cause and wound (42.3%) was the most common type of injuries. Our nationwide representative study showed that fire suppression and EMS workers are at greater risk of on-duty injuries compared to officers. We observed different injury characteristics compared to those reported in other countries.

ObjectiveWe aimed to assess the nature of association between job stress and occupational injuries among firefighters in Korea.DesignCross-sectional study.SettingWe conducted a nationwide survey using self-reported questionnaires in South Korea.ParticipantsA survey was conducted among 30 630 firefighters; 25 616 (83.6%) responded. Our study included firefighters who were 20–59 years old. Individuals with <12 months of current job experience and those with missing data were excluded; ultimately, 14 991 firefighters were analysed.ResultsAmong fire suppression personnel, high job demands (OR=1.49, 95% CI 1.25 to 1.77), high interpersonal conflicts (OR=1.18, 95% CI 1.02 to 1.37), a poor organisational system (OR=1.33, 95% CI 1.14 to 1.55), and a negative workplace environment (OR=1.41, 95% CI 1.21 to 1.64) were associated with the occurrence of occupational injury; high job demands (OR=1.22, 95% CI 1.01 to 1.47) were also associated with the frequency of injuries. Among emergency medical services personnel, high job demands (OR=1.26, 95% CI 1.03 to 1.54), high interpersonal conflicts (OR=1.40, 95% CI 1.19 to 1.66), a poor organisational system (OR=1.55, 95% CI 1.30 to 1.85), lack of reward (OR=1.43, 95% CI 1.21 to 1.69) and a negative workplace environment (OR=1.30, 95% CI 1.10 to 1.54) were associated with the occurrence of occupational injury; low job control (OR=1.20, 95% CI 1.04 to 1.38), high interpersonal conflicts (OR=1.18, 95% CI 1.03 to 1.36), lack of reward (OR=1.17, 95% CI 1.02 to 1.35) and a negative workplace climate (OR=1.16, 95% CI 1.01 to 1.34) were also associated with a greater number of injuries. Among officers, high job demands (OR=1.96, 95% CI 1.35 to 2.85) and a negative workplace environment (OR=1.54, 95% CI 1.13 to 2.10) were associated with the occurrence of occupational injuries; however, there was no significant correlation between job stress and the number of injuries.ConclusionsHigh job stress among firefighters was associated with both the occurrence of occupational injury, and also with an increased frequency of injuries. Therefore, job stress should be addressed to prevent occupational injuries among firefighters.

ATP citrate-lyase (ACL) is a key enzyme supplying acetyl-CoA for fatty acid and cholesterol synthesis. Its expression is drastically up-regulated when an animal is fed a low fat, high carbohydrate diet after prolonged fasting. In this report, we describe the role of sterol regulatory element-binding proteins (SREBPs) in the transactivation of the rat ACL promoter. ACL promoter activity was markedly stimulated by the overexpression of SREBP-1a and, to a lesser extent, by SREBP-2 in Alexander human hepatoma cells. The promoter elements responsive to SREBPs were located within the 55-base pair sequences from ؊114 to ؊60. The gel mobility shift assay revealed four SREBP-1a binding sites in this region. Of these four elements, the ؊102/؊94 region, immediately upstream of the inverted Y-box, and the ؊70/؊61 region, just adjacent to Sp1 binding site, played critical roles in SREBPs-mediated stimulation. The mutation in the inverted Y-box and the coexpression of dominant negative nuclear factor-Y (NF-Y) significantly attenuated the transactivation by SREBP-1a, suggesting that NF-Y binding is a prerequisite for SREBPs to activate the ACL promoter. However, the multiple Sp1 binding sites did not affect the transactivation of the ACL promoter by SREBPs. The binding affinity of SREBP-1a to SREs of the ACL promoter also was much higher than that of SREBP-2. The transactivation potencies of the chimeric SREBPs, of which the activation domains (70 amino acids of the amino terminus) were derived from the different species of their carboxyl-terminal region, were similar to those of SREBPs corresponding to their carboxyl termini. Therefore, it is suggested that the carboxyl-terminal portions of SREBPs containing DNA binding domains are important in determining their transactivation potencies to a certain promoter. ATP citrate-lyase (ACL)1 is a cytosolic enzyme that catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA (1). In liver and adipose tissue, this enzyme plays an important role in supplying acetyl-CoA for both fatty acid and cholesterol synthesis (2). As the specific inhibition of ACL in rats significantly decreases the plasma levels of triacylglycerol and cholesterol, ACL is expected to be a potential target for hypolipidemic intervention (3, 4). The activity of ACL is mainly regulated at the level of transcription by diet regimen and insulin, like other lipogenic enzymes, such as fatty acid synthase and acetyl-CoA carboxylase (5). The sequences of the 5Ј flanking region of the ACL gene are highly conserved in humans and rats, whereas there is no homology in the regions of the 5Ј untranslated region and the first intron, suggesting that transcription is regulated in the same manner in these two species (6, 7). Although ACL plays an important role in fatty acid and cholesterol biosynthesis and is highly controlled by diet at the transcription level, studies on the structure and function of this promoter have been very limited thus far.SREBPs are the transcription factors that regulate the transcription of ma...