Superfund Research Program
Effects Related Biomarkers of Toxic Exposures
Project Leader: Terrance J. Kavanagh
Grant Number: P42ES004696
Funding Period: 1995 - 2006
Investigators have sequenced approximately 5 kb and 2 kb of the 5' regulatory regions of mGLCLC and mGLCLR, respectively, and are characterizing these regions for structure and function. Using primer extension, scientists have mapped transcription start sites for both GLCLC and GLCLR and also have found a putative consensus ARE in GLCLC gene approximately 3 kb 5' of the transcription start site. There is also an ARE-like element approximately 300 bp 5' of the GLCLR transcription start site.
This team and others have found that GLCL is activated directly with oxidant exposure, in addition to being regulated at the transcriptional level. Using antisera developed with collaborators Jeff Ledbetter and Gary Scheiven (Bristol Myer Squibb), investigators found preliminary evidence for post-translational modification of GLCL with certain oxidizing treatments in cultured cells. The activation that occurs is not likely to involve kinase activation (no change in phosphorylation status was found).
Finally, the investigators assessed the expression of GLCL and other stress proteins in tissues from mice exposed to methyl mercury. Of the approximately 20 genes examined, GLCLC expression is most sensitive to MeHg exposure. Investigators also are examining patterns of expression of GLCLC and GLCLR (using in situ hybridization) and GSH (using a novel histochemical assay developed in the Analytical Cytology Core) in mouse embryos to characterize expression during development, and to ascertain whether this expression is correlated with GSH levels in various tissues.