Article

Activation of Nuclear Factor-kappa B signaling promotes cellular senescence

Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
Oncogene (Impact Factor: 8.56). 01/2011; 30(20):2356-66. DOI: 10.1038/onc.2010.611
Source: PubMed

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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Available from: Parmjit S Jat, Mar 18, 2014
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    • "Thus, in addition to the well-studied antiapoptotic activity of NF-kB (Finco et al., 1997; Hanson et al., 2004; Mayo et al., 1997), our current work highlights that during tumor initiation NF-kB protects transformed cells against a suppressive mechanism mediated by immune surveillance. RESULTS p65 Acts as a Tumor Suppressor in Precancerous Mouse Embryonic Fibroblasts Previous results showed that p65 acts as a tumor suppressor in cytogenetically normal mouse and human fibroblasts by regulating genomic stability through DNA repair (Rovillain et al., 2011; Wang et al., 2009). Consistent with these results, we observed that primary p65 À/À mouse embryonic fibroblasts (MEFs) escaped senescence and transitioned into a precancerous , immortalized state considerably faster than p65 +/+ littermate cells (Figure 1A). "
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    ABSTRACT: NF-kappa B is considered a major contributor to tumor development, but how this factor functions in the initial stages of oncogenesis is not clear. In a model of Ras-induced transformation, we probed NF-kappa B function as preneoplastic cells formed tumors in mice. As previously shown, the p65 subunit of NF-kappa B acts as a tumor suppressor in normal cells by sustaining senescence following DNA damage. Our current data reveal that, following immortalization, p65 switches to an oncogene by counteracting the surveillance properties of immune cells. NF-kappa B exerts this effect by protecting transformed cells against macrophage-derived proapoptotic factors, tumor necrosis factor, and nitric oxide. Additionally, NF-kappa B acts through transforming growth factor beta (TGF-beta) to mitigate T cell cytotoxicity and other factors to expand myeloid-derived suppressor cells. Together, these data suggest that NF-kappa B functions in the early stages of transformation by suppressing immune surveillance of both innate and adaptive immune cells, information that may be useful for targeted immunotherapies.
    Cell Reports 10/2014; 9(1). DOI:10.1016/j.celrep.2014.08.049 · 8.36 Impact Factor
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    • "Hardy and colleagues used cDNA microarrays to identify genes that were differentially expressed when conditionally immortal HMF3A fibroblasts underwent senescence growth arrest, followed by in silico promoter analysis of the differential genes and electrophoretic mobility shift assays (Hardy et al., 2005). Rovillain et al. (2011) extended this study using genomewide expression profiling, in conjunction with inactivation of the p16 INK4A -pRB and p53-p21 CIP1/WAF1/SDI1 tumor suppressor pathways, in HMF3A cells, to identify genes that were downregulated upon senescence . This data, coupled to bioinformatic transcription factor analysis, revealed that B-MYB was one of the most highly downregulated transcription factors upon senescence. "
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    ABSTRACT: Cellular senescence is a stable cell cycle arrest, caused by insults, such as: telomere erosion, oncogene activation, irradiation, DNA damage, oxidative stress, and viral infection. Extrinsic stimuli such as cell culture stress can also trigger this growth arrest. Senescence is thought to have evolved as an example of antagonistic pleiotropy, as it acts as a tumor suppressor mechanism during the reproductive age, but can promote organismal aging by disrupting tissue renewal, repair, and regeneration later in life. The mechanisms underlying the senescence growth arrest are broadly considered to involve p16INK4A-pRB and p53-p21CIP1/WAF1/SDI1 tumor suppressor pathways; but it is not known what makes the senescence arrest stable and what the critical downstream targets are, as they are likely to be key to the establishment and maintenance of the senescent state. MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has recently emerged as a potential candidate for regulating entry into senescence. Here, we review the evidence which indicates that loss of B-MYB expression has an important role in causing senescence growth arrest. We discuss how B-MYB acts, as the gatekeeper, to coordinate transit through the cell cycle, in conjunction with the multivulval class B (MuvB) complex and FOXM1 transcription factors. We also evaluate the evidence connecting B-MYB to the mTOR nutrient signaling pathway and suggest that inhibition of this pathway leading to an extension of healthspan may involve activation of B-MYB.
    Aging cell 06/2014; 13(5). DOI:10.1111/acel.12242 · 5.94 Impact Factor
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    • "Interestingly, recent publications postulated that senescence-associated and predominantly NF-κB-driven cytokines, collectively termed “senescence-associated secretory phenotype (SASP)”, may reinforce the senescent cell-cycle arrest (Acosta et al., 2008; Coppe et al., 2008; Kuilmann et al., 2008; Rovillain et al., 2011). These - on first sight - counter-intuitive, double-edged functions of NF-κB to promote both chemoresistance via anti-apoptosis and chemosensitivity via cellular senescence caught our attention to initiate an investigation to genetically determine the role of NF-κB in response to chemotherapy, with a special emphasis on TIS. "
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    ABSTRACT: The NF-κB pathway transcriptionally controls a large set of target genes that play important roles in cell survival, inflammation, and immune responses. While many studies showed anti-tumorigenic and pro-survival role of NF-κB in cancer cells, recent findings postulate that NF-κB participates in a senescence-associated cytokine response, thereby suggesting a tumor restraining role of NF-κB. In this review, we discuss implications of the NF-κB signaling pathway in cancer. Particularly, we emphasize the connection of NF-κB with cellular senescence as a response to chemotherapy, and furthermore, present examples how distinct oncogenic network contexts surrounding NF-κB produce fundamentally different treatment outcomes in aggressive B-cell lymphomas as an example.
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