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

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 I kappa B zeta, an atypical member of the inhibitor of NFkB proteins and selective coactivator of particular NFkB target genes, is an important regulator of SASP expression. Several models of DNA damage-and oncogene-induced senescence revealed a robust induction of I kappa B zeta expression. RNAi-mediated knockdown of I kappa B zeta impaired IL6 and IL8 expression, whereas transgenic I kappa B zeta expression resulted in enhanced SASP cytokine expression. Importantly, during senescence of I kappa B zeta 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 I kappa B zeta in SASP formation in both DNA damage-and oncogene-induced senescence.