title: Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP).
abstract: The major hallmark of cellular senescence is an irreversible cell cycle arrest and thus it is a potent tumor suppressor mechanism. Genotoxic insults, e.g. oxidative stress, are important inducers of the senescent phenotype which is characterized by an accumulation of senescence-associated heterochromatic foci (SAHF) and DNA segments with chromatin alterations reinforcing senescence (DNA-SCARS). Interestingly, senescent cells secrete pro-inflammatory factors and thus the condition has been called the senescence-associated secretory phenotype (SASP). Emerging data has revealed that NF-κB signaling is the major signaling pathway which stimulates the appearance of SASP. It is known that DNA damage provokes NF-κB signaling via a variety of signaling complexes containing NEMO protein, an NF-κB essential modifier, as well as via the activation of signaling pathways of p38MAPK and RIG-1, retinoic acid inducible gene-1. Genomic instability evoked by cellular stress triggers epigenetic changes, e.g. release of HMGB1 proteins which are also potent enhancers of inflammatory responses. Moreover, environmental stress and chronic inflammation can stimulate p38MAPK and ceramide signaling and induce cellular senescence with pro-inflammatory responses. On the other hand, two cyclin-dependent kinase inhibitors, p16INK4a and p14ARF, are effective inhibitors of NF-κB signaling. We will review in detail the signaling pathways which activate NF-κB signaling and trigger SASP in senescent cells.
authors.affiliation: Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland. antero.salminen@uef.fi
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.forename: Anu
authors.initials: A
authors.lastname: Kauppinen
authors.forename: Kai
authors.initials: K
authors.lastname: Kaarniranta
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D002518:Ceramides / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics*; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D002518:Ceramides; D019941:Cyclin-Dependent Kinase Inhibitor p16; D024243:HMGB1 Protein; C491731:IKBKG protein, human; D016328:NF-kappa B; D011971:Receptors, Immunologic; C491203:TXN protein, human; D025803:Tumor Suppressor Protein p14ARF; D013879:Thioredoxins; D051550:I-kappa B Kinase; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases