IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence
IκBζ is a regulator of the senescence-associated secretory phenotype in DNA damage- and oncogene-induced senescence
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DOI：
10.1242/jcs.128835
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发表时间：
2013-08-15
影响因子：
4
通讯作者：
Essmann, Frank
中科院分区：
文献类型：
--
作者：
Alexander, Eva;Hildebrand, Dominic G.;Essmann, Frank
细胞衰老是一种持续的细胞周期停滞状态，已被确定为重要的抗肿瘤屏障。衰老细胞分泌各种生长因子和细胞因子，如IL 6和IL 8，它们共同构成衰老相关分泌表型（SASP）。SASP可以向肿瘤环境发出信号并引发肿瘤细胞的免疫介导的清除，或者根据情况，可能潜在地促进肿瘤进展。尽管SASP对肿瘤生物学的重要性，但其调节仍然相对未知。在这里，我们表明，I κ B zeta，一个非典型的成员的抑制剂的NF κ B蛋白和选择性共激活剂的特定NF κ B靶基因，是一个重要的调节SASP的表达。DNA损伤和癌基因诱导衰老的几种模型显示I κ B zeta表达的强烈诱导。RNAi介导的I κ B zeta基因敲低损害了IL 6和IL 8的表达，而转基因I κ B zeta基因表达导致SASP细胞因子表达增强。重要的是，在I κ B zeta基因敲除细胞衰老期间，IL 6和IL 8的诱导，而不是细胞周期抑制剂p21（WAF/CIP 1）的诱导，被完全消除。因此，我们提出了一个重要的和迄今未被赞赏的作用，I κ B zeta在SASP的形成在DNA损伤和癌基因诱导的衰老。
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.