Loss of NF-κB control and repression of Prdx6 gene transcription by reactive oxygen species-driven SMAD3-mediated transforming growth factor β signaling

Nigar Fatima, Eri Kubo, Yoshihiro Takamura, Keiichi Ishihara, Claudia Garcia, David C. Beebe, Dhirendra P. Singh

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

In summary, the present study unveiled a novel mechanism of Prdx6 repression, showing the involvement of Smad3-mediated TGFβ-induced dominant repressive signaling in cells facing oxidative stress. Additionally, we propose a novel role for NF-κB as a stress-sensing molecule that determines optimal regulation of Prdx6 transcription that may require fine tuning to avoid overshooting the desired beneficial effects to the point of perturbing the delicate redox balance necessary for the maintenance of cellular functions, at least in eye lens/LECs. Findings of this study add to knowledge of how the gene network is changed during aging or oxidative stress and how these changes act to turn survival signaling into deleterious signaling. Although a more complete understanding of LEC cellular response to oxidative stress is required, we believe that these events are causally related (i.e. that the age-related reduction in PRDX6 in lens tissues leads to oxidative damage of membrane or cytosolic or nuclear factors important to maintain normal lens physiology). As a consequence of this damage, the cell homeostatic system fails, leading to cataractogenesis or other degenerative disorders. The outcome of the study described here should provide significant insight into the progression and plausible etiology of oxidative stress-associated disorders and deliver the background for developing antioxidant and/or transcription factor(s) modulation-based therapy for preventing or treating cataract and age-associated diseases in general.

Original languageEnglish (US)
Pages (from-to)22758-22772
Number of pages15
JournalJournal of Biological Chemistry
Volume284
Issue number34
DOIs
StatePublished - Aug 21 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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