Chronic NF-kappaB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response.
Chronic NF-kappaB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response.
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DOI：
10.1016/j.mad.2009.04.002
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发表时间：
2009-07
影响因子：
5.3
通讯作者：
Kolettas E
中科院分区：
文献类型：
--
作者：
Batsi C;Markopoulou S;Vartholomatos G;Georgiou I;Kanavaros P;Gorgoulis VG;Marcu KB;Kolettas E
正常细胞分裂为有限的世代，之后进入不可逆转的生长停滞状态，称为复制性衰老。复制性衰老是由于端粒侵蚀引起的，而正常的人成纤维细胞可以在癌基因激活的情况下经历应激诱导的衰老，称为癌基因诱导衰老(OIS)。Replicative和OIS都启动DNA损伤检查点反应(DDR)，导致p53-p21Cip1/Waf1通路的激活。然而，虽然核因子-kappaB(NF-κB)信号通路参与了DDR，但其在OIS中的作用尚未被研究。在这里，我们发现致癌的Ha-RasV12通过激活DDR来促进IMR-90正常人二倍体成纤维细胞的早衰，从而验证了OIS的经典模型。然而，通过抑制Ha-βV12诱导的反义寡核苷酸反应，IKKβ突变蛋白(IKK RasV12)的表达显著延迟了细胞的OIS。因此，我们的实验发现，在慢性激活规范的NF-κB信号以克服正常原代人类成纤维细胞的抗增殖OIS反应方面，具有重要的选择性优势。
Normal cells divide for a limited number of generations, after which they enter a state of irreversible growth arrest termed replicative senescence. While replicative senescence is due to telomere erosion, normal human fibroblasts can undergo stress-induced senescence in response to oncogene activation, termed oncogene-induced senescence (OIS). Both, replicative and OIS, initiate a DNA damage checkpoint response (DDR) resulting in the activation of the p53-p21Cip1/Waf1 pathway. However, while the nuclear factor-kappaB (NF-κB) signaling pathway has been implicated in DDR, its role in OIS has not been investigated. Here, we show that oncogenic Ha-RasV12 promoted premature senescence of IMR-90 normal human diploid fibroblasts by activating DDR, hence verifying the classical model of OIS. However, enforced expression of a constitutively active IKKβ T-loop mutant protein (IKKβca), significantly delayed OIS of IMR-90 cells by suppressing Ha-RasV12 instigated DDR. Thus, our experiments have uncovered an important selective advantage in chronically activating canonical NF-κB signaling to overcome the anti-proliferative OIS response of normal primary human fibroblasts.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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