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TGFβ1‐induced suppression of glutathione antioxidant defenses in hepatocytes: caspase‐dependent posttranslational and caspase‐independent transcriptional regulatory mechanisms
Author(s) -
Franklin Christopher C.,
Rosenfeld-Franklin Maryland E.,
White Collin,
Kavanagh Terrance J.,
Fausto Nelson
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0867fje
Subject(s) - gclc , glutathione , microbiology and biotechnology , gclm , oxidative stress , caspase , biology , chemistry , programmed cell death , apoptosis , biochemistry , enzyme
TGFβ1‐induced hepatocyte apoptosis involves the production of reactive oxygen species. An effective cellular defense mechanism against oxidative stress is the tripeptide glutathione (GSH), and the rate‐limiting step in GSH biosynthesis is catalyzed by the heterodimeric holoenzyme glutamate cysteine ligase (GCL). Here, we demonstrate that TGFβ1‐induced apoptosis in the TAMH murine hepatocyte cell line is accompanied by both the cleavage and loss of the catalytic subunit of GCL (GCLC) and the down‐regulation of GCLC gene expression resulting in a reduction in GCL activity and depletion of intracellular GSH. TGFβ1‐induced apoptosis is also accompanied by a reduction in Bcl‐X L , an effect that may facilitate TGFβ1‐induced apoptosis as Bcl‐X L overexpression inhibits TGFβ1‐induced caspase activation and cell death. Interestingly, Bcl‐X L overexpression prevents TGFβ1‐induced cleavage of GCLC protein but not down‐regulation of GCLC mRNA. Furthermore, TGFβ1‐induced down‐regulation of GCLC mRNA is prevented by inhibition of histone deacetylase activity, suggesting that this is an active repression of GCLC gene transcription. These findings suggest that the suppression of GSH antioxidant defenses associated with the caspase‐dependent cleavage of GCLC protein, caspase‐independent suppression of GCLC gene expression, and depletion of intracellular GSH may play a role in enhancing TGFβ1‐induced oxidative stress and potentiating apoptotic cell death.