| Abstrakt: |
The thiol-containing tripeptide glutathione (GSH) provides the most abundant redox buffer in eukaryotic cells. Glutathione homeostasis reflects a complex interplay of synthesis, transport, storage, oxidation/reduction, further metabolism, and catabolism. To identify molecular mechanisms that coordinate these poorly understood processes, we are using a comparative genomic approach focused on Ciona intestinalis. Adult animals are sessile filter feeders and routinely encounter natural marine toxins chemically similar to known inducers of human detoxification genes. We hypothesize that functional, noncoding elements in the Ciona genome, which regulate glutathione homeostasis that are conserved with higher vertebrates may be useful for the identification of novel transcriptional networks underlying genetic susceptibility to environmentally triggered diseases. Initial efforts to annotate genes contributing to GSH homeostasis have identified Ciona homologs of GCLC, GCLM, GSS, GGT, the dipeptidases (ANPEP, DPEP1, LAP3), GPX1, GSR, GSTA1, GSTM1, GSTP1, GLRX, xCT, OATP1B1, and MRP2 and known regulators including Nrf2, KEAP1, small MAF, NFκB, AP-1, AHR, FXR, PXR, RXR, and VDR. In addition, RT-PCR data demonstrate constitutive expression of GCLC, GCLM, and GSTM1 in the branchial basket, GI tract and heart as well as upregulation of GCLC and GCLM by the prototypieal antioxidant TBHQ in these tissues. [ABSTRACT FROM AUTHOR] |
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