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Chronic NF-kappaB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response.


ABSTRACT: 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-p21(Cip1/Waf1) pathway. However, while the nuclear factor-kappaB (NF-kappaB) 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 IKKbeta T-loop mutant protein (IKKbetaca), 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-kappaB signaling to overcome the anti-proliferative OIS response of normal primary human fibroblasts.

SUBMITTER: Batsi C 

PROVIDER: S-EPMC2765928 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Chronic NF-kappaB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response.

Batsi Christina C   Markopoulou Soultana S   Vartholomatos George G   Georgiou Ioannis I   Kanavaros Panagiotis P   Gorgoulis Vassilis G VG   Marcu Kenneth B KB   Kolettas Evangelos E  

Mechanisms of ageing and development 20090503 7


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-p21(Cip1/Waf1) pathway. However, while  ...[more]

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