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IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence.

Authors
  • Alexander, Eva
  • Hildebrand, Dominic G
  • Kriebs, Anna
  • Obermayer, Kerstin
  • Manz, Marianne
  • Rothfuss, Oliver
  • Schulze-Osthoff, Klaus
  • Essmann, Frank
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Aug 15, 2013
Volume
126
Issue
Pt 16
Pages
3738–3745
Identifiers
DOI: 10.1242/jcs.128835
PMID: 23781024
Source
Medline
Keywords
License
Unknown

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.

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