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

Oncogene volume 20, pages 2178–2185 (2001)Cite this article

Abstract

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 pro-apoptotic genes by NF-κB and increased cell survival during ER stress as well as identify a distinct NF-κB regulated cell survival pathway.

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Abbreviations

GADD153/CHOP:

growth arrest and DNA damage inducible gene 153/CEBP homology protein

NF-κB:

Nuclear factor-kappaB

IκB:

Inhibitor-of-kappaB

EMSA:

electrophoretic mobility shift assay

ER:

endoplasmic reticulum

IL-1:

Interleukin 1.

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Acknowledgements

We thank D Baltimore, K Cornetta, WC Greene, A Hoffmann and N Holbrook for various reagents. We also thank J Dunn and P Bhat-Nakshatri for technical assistance and RA Campbell for critical reading of the manuscript. This work is supported in part by American Cancer Society (RPG-00-122-01-TBE), Charles E Culpeper Foundation, Phi Beta Psi Sorority and The Catherine Peachy Fund, Inc. (to H Nakshatri).

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Authors and Affiliations

  1. Department of Medicine, Indiana University School of Medicine, 46202, Indianapolis, IN, USA

    Shinichi Nozaki & George W Sledge, Jr

  2. Department of Pathology, Indiana University School of Medicine, 46202, Indianapolis, IN, USA

    George W Sledge, Jr

  3. Department of Surgery, Indiana University School of Medicine, 46202, IN, USA

    Harikrishna Nakshatri

  4. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 46202, Indianapolis, IN

    Harikrishna Nakshatri

  5. Walther Oncology Center, Indiana University School of Medicine, 46202, Indianapolis, IN, USA

    Harikrishna Nakshatri

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Nozaki, S., Sledge, Jr, G. & Nakshatri, H. Repression of GADD153/CHOP by NF-κB: a possible cellular defense against endoplasmic reticulum stress-induced cell death. Oncogene 20, 2178–2185 (2001). https://doi.org/10.1038/sj.onc.1204292

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