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

作者：Batsi Christina; Markopoulou Soultana; Vartholomatos George; Georgiou Ioannis; Kanavaros Panagiotis; Gorgoulis Vassilis G; Marcu Kenneth B^*; Kolettas Evangelos

来源：Mechanisms of Ageing and Development, 2009, 130(7): 409-419.

DOI：10.1016/j.mad.2009.04.002

• Human fibroblasts
• Ha-RasV12
• IKK beta ca
• NF-kappa B
• Senescence
• DNA damage

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(Cip/Waf1) pathway. However, while the nuclear factor-kappaB (NF-kappa B) 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 IKK beta T-loop mutant protein (IKK beta ca), 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-kappa B signaling to overcome the anti-proliferative OIS response of normal primary human fibroblasts.

• 出版日期2009-7