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TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death

Tumor necrosis factor α (TNF-α) receptor–associated factor 2 (TRAF2) regulates activation of the c-Jun N-terminal kinase (JNK)/c-Jun and the inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling cascades in response to TNF-α stimulation. Gene knockout studies have revealed that TRAF2 inhi...

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Autores principales: Zhang, Laiqun, Blackwell, Ken, Altaeva, Aliya, Shi, Zhaohui, Habelhah, Hasem
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016971/
https://www.ncbi.nlm.nih.gov/pubmed/21119000
http://dx.doi.org/10.1091/mbc.E10-06-0556
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author Zhang, Laiqun
Blackwell, Ken
Altaeva, Aliya
Shi, Zhaohui
Habelhah, Hasem
author_facet Zhang, Laiqun
Blackwell, Ken
Altaeva, Aliya
Shi, Zhaohui
Habelhah, Hasem
author_sort Zhang, Laiqun
collection PubMed
description Tumor necrosis factor α (TNF-α) receptor–associated factor 2 (TRAF2) regulates activation of the c-Jun N-terminal kinase (JNK)/c-Jun and the inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling cascades in response to TNF-α stimulation. Gene knockout studies have revealed that TRAF2 inhibits TNF-α–induced cell death but promotes oxidative stress–induced apoptosis. Here we report that TNF-α and oxidative stress both induce TRAF2 phosphorylation at serines 11 and 55 and that this dual phosphorylation promotes the prolonged phase of IKK activation while inhibiting the prolonged phase of JNK activation. Prolonged IKK activation trigged by TNF-α plays an essential role in efficient expression of a subset of NF-κB target genes but has no substantial role in TNF-α–induced cell death. On the other hand, TRAF2 phosphorylation in response to oxidative stress significantly promotes cell survival by inducing prolonged IKK activation and by inhibiting the prolonged phase of JNK activation. Notably, stable expression of phospho-null mutant TRAF2 in cancer cells leads to an increase in the basal and inducible JNK activation and B-cell lymphoma 2 (Bcl-2) phosphorylation. In addition, exposure of cells expressing phospho-null mutant TRAF2 to sublethal oxidative stress results in a rapid degradation of Bcl-2 and cellular inhibitor of apoptosis 1 as well as significantly increased cell death. These results suggest that TRAF2 phosphorylation is essential for cell survival under conditions of oxidative stress.
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spelling pubmed-30169712011-03-16 TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death Zhang, Laiqun Blackwell, Ken Altaeva, Aliya Shi, Zhaohui Habelhah, Hasem Mol Biol Cell Articles Tumor necrosis factor α (TNF-α) receptor–associated factor 2 (TRAF2) regulates activation of the c-Jun N-terminal kinase (JNK)/c-Jun and the inhibitor of κB kinase (IKK)/nuclear factor κB (NF-κB) signaling cascades in response to TNF-α stimulation. Gene knockout studies have revealed that TRAF2 inhibits TNF-α–induced cell death but promotes oxidative stress–induced apoptosis. Here we report that TNF-α and oxidative stress both induce TRAF2 phosphorylation at serines 11 and 55 and that this dual phosphorylation promotes the prolonged phase of IKK activation while inhibiting the prolonged phase of JNK activation. Prolonged IKK activation trigged by TNF-α plays an essential role in efficient expression of a subset of NF-κB target genes but has no substantial role in TNF-α–induced cell death. On the other hand, TRAF2 phosphorylation in response to oxidative stress significantly promotes cell survival by inducing prolonged IKK activation and by inhibiting the prolonged phase of JNK activation. Notably, stable expression of phospho-null mutant TRAF2 in cancer cells leads to an increase in the basal and inducible JNK activation and B-cell lymphoma 2 (Bcl-2) phosphorylation. In addition, exposure of cells expressing phospho-null mutant TRAF2 to sublethal oxidative stress results in a rapid degradation of Bcl-2 and cellular inhibitor of apoptosis 1 as well as significantly increased cell death. These results suggest that TRAF2 phosphorylation is essential for cell survival under conditions of oxidative stress. The American Society for Cell Biology 2011-01-01 /pmc/articles/PMC3016971/ /pubmed/21119000 http://dx.doi.org/10.1091/mbc.E10-06-0556 Text en © 2011 Zhang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,“ “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Zhang, Laiqun
Blackwell, Ken
Altaeva, Aliya
Shi, Zhaohui
Habelhah, Hasem
TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death
title TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death
title_full TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death
title_fullStr TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death
title_full_unstemmed TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death
title_short TRAF2 phosphorylation promotes NF-κB–dependent gene expression and inhibits oxidative stress-induced cell death
title_sort traf2 phosphorylation promotes nf-κb–dependent gene expression and inhibits oxidative stress-induced cell death
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016971/
https://www.ncbi.nlm.nih.gov/pubmed/21119000
http://dx.doi.org/10.1091/mbc.E10-06-0556
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