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

Batsi, C./ Markopoulou, S./ Vartholomatos, G./ Georgiou, I./ Kanavaros, P./ Gorgoulis, V. G./ Marcu, K. B./ Kolettas, E.

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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: *Cell Aging,Cell Proliferation,Cells, Cultured,Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism,*DNA Damage,Fibroblasts/cytology/*metabolism,Humans,NF-kappa B/genetics/*metabolism,Oncogene Protein p21(ras)/genetics/*metabolism,*Signal Transduction,Tumor Suppressor Protein p53/genetics/metabolism
ISSN: 1872-6216
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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