title: IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence.
abstract: Cellular senescence, a state of sustained cell cycle arrest, has been identified as an important anti-tumor barrier. Senescent cells secrete various growth factors and cytokines, such as IL6 and IL8, which collectively constitute the senescence-associated secretory phenotype (SASP). The SASP can signal to the tumor environment and elicit the immune-mediated clearance of tumor cells or, depending on the context, could potentially promote tumor progression. Despite the importance of the SASP to tumor biology, its regulation remains relatively unknown. Here, we show that IκBζ, an atypical member of the inhibitor of NFκB proteins and selective coactivator of particular NFκB target genes, is an important regulator of SASP expression. Several models of DNA damage- and oncogene-induced senescence revealed a robust induction of IκBζ expression. RNAi-mediated knockdown of IκBζ impaired IL6 and IL8 expression, whereas transgenic IκBζ expression resulted in enhanced SASP cytokine expression. Importantly, during senescence of IκBζ knockout cells induction of IL6 and IL8, but not of the cell cycle inhibitor p21(WAF/CIP1), was completely abolished. Thus, we propose an important and hitherto unappreciated role of IκBζ in SASP formation in both DNA damage- and oncogene-induced senescence.
authors.affiliation: Interfaculty Institute for Biochemistry, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Alexander
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Hildebrand
authors.forename: Anna
authors.initials: A
authors.lastname: Kriebs
authors.forename: Kerstin
authors.initials: K
authors.lastname: Obermayer
authors.forename: Marianne
authors.initials: M
authors.lastname: Manz
authors.forename: Oliver
authors.initials: O
authors.lastname: Rothfuss
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulze-Osthoff
authors.forename: Frank
authors.initials: F
authors.lastname: Essmann
mesh_terms: D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D009857:Oncogenes; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins
keywords: Cytokines; DNA damage; IκBζ; NFκB; SASP; Senescence