Dataset Information

Activation of nuclear factor-kappa B signalling promotes cellular senescence.

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)-?B suggesting that senescence was associated with activation of the NF-?B pathway. Direct perturbation of this pathway bypasses growth arrest indicating that activation of NF-?B signalling has a causal role in promoting senescence.

SUBMITTER: Rovillain E

PROVIDER: S-EPMC3080811 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activation of nuclear factor-kappa B signalling promotes cellular senescence.

Rovillain E E Mansfield L L Caetano C C Alvarez-Fernandez M M Caballero O L OL Medema R H RH Hummerich H H Jat P S PS

Oncogene 20110117 20

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 senesce ...[more]

PMID: 21242976

Similar Datasets

Project description:Both the aging of animals and the senescence of cultured cells involve an altered pattern of gene expression, suggesting changes in transcription factor regulation. We studied age-related changes in transcription factors nuclear factor (NF)-kappa B, activator protein factor-1 (AP-1) and Sp-1 by using electrophoretic mobility shift binding assays; we also analysed changes in the protein components of NF-kappa B complex with Western blot assays. Nuclear and cytoplasmic extracts were prepared from heart, liver, kidney and brain of young adult and old NMRI mice and Wistar rats as well as from presenescent, senescent and simian virus 40-immortalized human WI-38 fibroblasts. Aging of both mice and rats induced a strong and consistent increase in the nuclear binding activity of NF-kappa B factor in all tissues studied, whereas those of AP-1 and Sp-1 decreased, e.g. in liver. Protein levels of p50, p52 and p65 components of the NF-kappa B complex did not show any age-associated changes in the cytoplasmic fraction but in the nuclear fraction the level of p52 strongly increased in heart and liver during aging. The protein levels of inhibitory I kappa B-alpha and Bcl-3 components were not affected by aging in any of the tissues studied. Replicative cellular senescence of human WI-38 fibroblasts induced a strong decrease in nuclear NF-kappa B, AP-1 and Sp-1 binding activities. Protein levels of p50 and p52 components of NF-kappa B complex were decreased in the nuclear fraction of senescent WI-38 fibroblasts but in the cytoplasm of senescent fibroblasts the level of p65 protein was increased. Cellular senescence also slightly decreased the protein levels of I kappa B-alpha and Bcl-3. Transfection assays with NF-kappa B-enhancer-driven chloramphenicol acetyltransferase reporter gene showed a significant down-regulation of NF-kappa B promoter activity in senescent WI-38 fibroblasts. Results suggest that the aging process might be regulated differently in tissues and cultured fibroblasts, perhaps reflecting differences between mitotic and post-mitotic cells. In tissues, aging seems to involve specific changes in the regulation of NF-kappa B components and perhaps also changes in the DNA-binding affinities of the NF-kappa B complex.

Dataset Information

Activation of nuclear factor-kappa B signalling promotes cellular senescence.

Publications

Activation of nuclear factor-kappa B signalling promotes cellular senescence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets