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| Science Forum Index » Life Extension Forum » TGF-Beta in CFS, consistently upregulated, and depresses pha |
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 Posted: Wed Dec 07, 2005 9:48 pm |
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In CFS the most consistent finding is increased TGF-Beta1. According to
this study, this could be a major cause of CFS problems if so.
Dysregulation of GSH, Glutamate, Gaba and phase II detox would occur.
All these things are messed in CFS and FM.
Any thoughts? Could NRF2 inducers help, if TGF-Beta is pushing back?
Is there any way to inhibit TGF-Beta?
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Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding
Phase II detoxifying proteins.
Bakin AV, Stourman NV, Sekhar KR, Rinehart C, Yan X, Meredith MJ,
Arteaga CL, Freeman ML.
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo,
NY 14263, USA. andrei.bakin@roswellpark.org
This study provides evidence that in mammary epithelial cells the
pluripotent cytokine TGF-beta1 repressed expression of multiple genes
involved in Phase II detoxification. GCLC, the gene that encodes the
catalytic subunit of the enzyme glutamate cysteine ligase, the
rate-limiting enzyme in the biosynthesis of glutathione, was used as a
molecular surrogate for investigating the mechanisms by which TGF-beta
suppressed Phase II gene expression. TGF-beta was found to suppress
luciferase reporter activity mediated by the human GCLC proximal
promoter, as well as reporter activity mediated by the GCLC antioxidant
response element, ARE4. TGF-beta downregulated expression of endogenous
GCLC mRNA and GCLC protein. TGF-beta suppression of the Phase II genes
correlated with a decrease in cellular glutathione and an increase in
cellular reactive oxygen species. Ectopic expression of constitutively
active Smad3E was sufficient to inhibit both reporters in the absence
of TGF-beta, whereas dominant negative Smad3A blocked TGF-beta
suppression. Smad3E suppressed Nrf2-mediated activation of the GCLC
reporter. We demonstrate that TGF-beta increased ATF3 protein levels,
as did transient overexpression of Smad3E. Ectopic expression of ATF3
was sufficient to suppress the GCLC reporter activity, as well as
endogenous GCLC expression. These results demonstrate that Smad3-ATF3
signaling mediates TGF-beta repression of ARE-dependent Phase II gene
expression and potentially provide critical insight into mechanisms
underlying TGF-beta1 function in carcinogenesis, tissue repair, and
fibrosis.
PMID: 15629866 [PubMed - indexed for MEDLINE]
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