Repression of GADD153/CHOP by NF-κB: A possible cellular defense against endoplasmic reticulum stress-induced cell death

Shinichi Nozaki, George W. Sledge, Harikrishna Nakshatri

Research output: Contribution to journalArticle

97 Scopus citations


Exposure of mammalian cells to ultraviolet light, nutrient deprived culture media, hypoxia, environmental toxicants such as methyl mercury, methyl methanesulfonate, crocodilite asbestos or the agents that disrupt the function of endoplasmic reticulum (ER) leads to activation of the pro-apoptotic transcription factor GADD153/CHOP. Paradoxically, several of these agents also induce the anti-apoptotic transcription factor NF-κB. In this report, we demonstrate that NF-κB inhibits GADD153 activation in breast cancer cells exposed to nutrient deprived media, tunicamycin (which blocks protein folding in ER) or calcium ionopore (which depletes calcium stores in ER). Basal and calcium ionopore-induced GADD153 expression was more pronounced in fibroblasts obtained from mouse embryos lacking in p65 subunit of NF-κB compared to fibroblasts from wild type littermate embryos. Moreover, p65-/fibroblasts were killed more efficiently by calcium ionopore and tunicamycin but not hydrogen peroxide compared to wild type fibroblasts. We also show that parthenolide, a NF-κB inhibitor, sensitizes breast cancer cells to tunicamycin. Transient transfection assay revealed that the p65 subunit but not the p50 subunit of NF-κB represses GADD153 promoter activity. These results establish a correlation between repression of proapoptotic genes by NF-κB and increased cell survival during ER stress as well as identify a distinct NF-κB regulated cell survival pathway.

Original languageEnglish (US)
Pages (from-to)2178-2185
Number of pages8
Issue number17
StatePublished - Apr 19 2001


  • Apoptosis
  • Endoplasmic reticulum stress
  • GADD153/CHOP
  • NF-κB
  • Transcription repression

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Fingerprint Dive into the research topics of 'Repression of GADD153/CHOP by NF-κB: A possible cellular defense against endoplasmic reticulum stress-induced cell death'. Together they form a unique fingerprint.

  • Cite this