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Activation of nuclear factor-kappa B signalling promotes cellular senescence

Oncogene volume 30, pages 2356–2366 (2011)Cite this article

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Abstract

Cellular senescence is a programme of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, of major clinicopathological relevance, are unknown. We combined genome-wide expression profiling with genetic complementation to identify genes that are differentially expressed when conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. This identified 816 up and 961 downregulated genes whose expression was reversed when senescence was bypassed. Overlay of this data set with the meta-signatures of genes upregulated in cancer showed that nearly 50% of them were downregulated upon senescence showing that even though overcoming senescence may only be one of the events required for malignant transformation, nearly half of the genes upregulated in cancer are related to it. Moreover 65 of the up and 26 of the downregulated genes are known downstream targets of nuclear factor (NF)-κB suggesting that senescence was associated with activation of the NF-κB pathway. Direct perturbation of this pathway bypasses growth arrest indicating that activation of NF-κB signalling has a causal role in promoting senescence.

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Acknowledgements

We are indebted to AM Neville, A Baldwin, P Meier, M Resnicoff and N Perkins for advice, helpful discussions and critical reading of the manuscript. We thank J Downward, X Lu, P Meier, G Towers and C King (the UCL shRNA library core facility) for providing reagents. We are grateful to E Ortenberg and J White of Biotrove Inc. for the qPCR analysis, S Shah and A Grigoriadis for bioinformatic analysis and R Young for graphics. PSJ gratefully acknowledges financial support from the Wellcome Trust (078305) and an equipment grant from the Brain Research Trust.

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Authors and Affiliations

  1. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    E Rovillain, L Mansfield, C Caetano & P S Jat

  2. Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands

    M Alvarez-Fernandez & R H Medema

  3. Ludwig Institute for Cancer Research Ltd, New York, NY, USA

    O L Caballero

  4. MRC Prion Unit, UCL Institute of Neurology, London, UK

    H Hummerich

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  1. E Rovillain
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Correspondence to P S Jat.

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Rovillain, E., Mansfield, L., Caetano, C. et al. Activation of nuclear factor-kappa B signalling promotes cellular senescence. Oncogene 30, 2356–2366 (2011). https://doi.org/10.1038/onc.2010.611

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