Occupational silica exposure as a risk factor for scleroderma: a meta-analysis.

OBJECTIVES: Among potential environmental risk factors for systemic sclerosis (SSc), occupational exposures have received some attention. In this meta-analysis, we examined the association between SSc and occupational exposure to silica. METHODS: We searched Medline, Toxline, BIOSIS, and Embase (1949 and November 2009) for original articles published in any language. Sixteen studies are included in the analysis, of which, 3 are cohort studies, 9 case-control and 4 are of other designs. The combined estimator of relative risk (CERR) and 95% confidence interval (CI) were calculated using fixed or random effect models. RESULTS: Significant heterogeneity was detected (I (2) = 97.2%; P < 0.01), and the CERR was 3.20 (95% CI, 1.89-5.43). The CERR for studies in females was 1.03 (95% CI, 0.74-1.44) and was 3.02 (95% CI, 1.24-7.35) for males. The CERR for case-control studies was 2.24 (95% CI, 1.65-3.31) and was 15.49 (95% CI, 4.54-52.87) for cohort studies. CONCLUSIONS: The findings suggest that silica exposure may be a significant risk factor for developing SSc and specifically in males. Further observational studies examining the role of occupational silica exposure in the context of other risk factors are needed.

Functional expression and analysis of the pancreatic transcription factor PDX-1 in yeast.

The pancreas-specific transcription factor Pdx-1 is important for pancreas development and beta-cell specific gene expression in insulin-producing cells. We have expressed the mouse PDX-1 gene in the yeast Saccharomyces cerevisiae and characterized its functional domains. Pdx-1 functions as a strong activator in yeast and stimulates gene expression by more than 80-fold. The transcriptional activation domain of Pdx-1 is located within the first 144 amino-terminal amino acids. Pdx-1 is also able to bind and activate transcription from the A3 element of the human insulin gene promoter in yeast. Analysis of the effects of two-point mutations (Q59L and R197H) in the PDX-1 gene found in type II diabetes patients showed that both point mutations interfere with the ability of Pdx-1 to bind to DNA and to activate transcription in yeast.

Glucose-mediated phosphorylation converts the transcription factor Rgt1 from a repressor to an activator.

Glucose, the most abundant carbon and energy source, regulates the expression of genes required for its own efficient metabolism. In the yeast Saccharomyces cerevisiae, glucose induces the expression of the hexose transporter (HXT) genes by modulating the activity of the transcription factor Rgt1 that functions as a repressor when glucose is absent. However, in the presence of high concentrations of glucose, Rgt1 is converted from a repressor to an activator and is required for maximal induction of HXT1 gene expression. We report that Rgt1 binds to the HXT1 promoter only in the absence of glucose, suggesting that Rgt1 increases HXT1 gene expression at high levels of glucose by an indirect mechanism. It is likely that Rgt1 stimulates the expression of an activator of the HXT1 gene at high concentrations of glucose. In addition, we demonstrate that Rgt1 becomes hyperphosphorylated in response to high glucose levels and that this phosphorylation event is required for Rgt1 to activate transcription. Furthermore, Rgt1 lacks the glucose-mediated phosphorylation in the snf3 rgt2 and grr1 mutants, which are defective in glucose induction of HXT gene expression. In these mutants, Rgt1 behaves as a constitutive repressor independent of the carbon source. We conclude that phosphorylation of Rgt1 in response to glucose is required to abolish the Rgt1-mediated repression of the HXT genes and to convert Rgt1 from a transcriptional repressor to an activator.