Cited by 732NF-κB Signaling PathwaysCell death mechanisms and regulationSignaling Pathways in Disease

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Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling

De Smaele, Enrico, Zazzeroni, Francesca, Papa, Salvatore, Nguyen, Dung U., Jin, Rongguan, Jones, Joy, Cong, Rong, Franzoso, Guido·2001·Nature

DOI 10.1038/35104560

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Abstract

In addition to coordinating immune and inflammatory responses, NF-kappaB/Rel transcription factors control cell survival. Normally, NF-kappaB dimers are sequestered in the cytoplasm by binding to inhibitory IkappaB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IkappaBs. Activation of NF-kappaB antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor. The anti-apoptotic activity of NF-kappaB is also crucial to oncogenesis and to chemo- and radio-resistance in cancer. Cytoprotection by NF-kappaB involves the activation of pro-survival genes; however, its basis remains poorly understood. Here we report that NF-kappaB complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade, thus establishing a link between the NF-kappaB and the JNK pathways. This link involves the transcriptional upregulation of gadd45beta/myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-kappaB-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-kappaB complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-alpha.

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Authors: De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D. U., Jin, R., Jones, J., Cong, R., & Franzoso, G.
Affiliations: University of Chicago (US)
Corresponding author: Franzoso, Guido
ORCID: Zazzeroni, Francesca
Papa, Salvatore
Franzoso, Guido
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2001-11
Volume: 414
Issue: 6861
Pages: 308-313
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/35104560
OpenAlex: W1563090311
Cited by: 732
References: 30
Citations by year: 2026: 6 · 2025: 7 · 2024: 14 · 2023: 11 · 2022: 12 · 2021: 16 · 2020: 10 · 2019: 16 · 2018: 24 · 2017: 12 · 2016: 25 · 2015: 16 · 2014: 18 · 2013: 29 · 2012: 22
FWCI: 22.58
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords: NF-κB, GADD45B, JNK signaling, apoptosis, TNF receptor, TNF-α, cell survival, transcriptional regulation, IκB, death receptors, anti-apoptotic signaling
MeSH terms: GADD45 Proteins, Animals, Antigens, Differentiation, Cell Line, Cell Survival, Cycloheximide, Gene Expression Regulation, Protein Synthesis Inhibitors, Tumor Necrosis Factor-alpha, NF-kappa B, 3T3 Cells, Apoptosis, Receptors, Tumor Necrosis Factor, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, JNK Mitogen-Activated Protein Kinases, Mice

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Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling

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