Journal
CELLULAR SIGNALLING
Volume 24, Issue 3, Pages 708-717Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2011.11.004
Keywords
Telomerase; Reactive oxygen species; TNF-alpha; NF-kappa B
Categories
Funding
- de Duve Institute
- Fonds National de la Recherche Scientifique (FNRS), Belgium
- FRIA/FNRS
- Centre du Cancer, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium
- Televie
- FNRS
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In addition to its well-established role in telomere synthesis, telomerase exerts non-canonical functions that may promote cancer and stem cell survival, notably by lowering reactive oxygen species (ROS) levels and acting as transcriptional cofactor in Wnt-beta-catenin signaling pathway. We investigated the impact of telomerase on ROS-dependent and -independent cellular responses to Tumor Necrosis Factor-alpha (TNF-alpha), a potent inducer of endogenous ROS production and activator of NF-kappa B signaling pathway. Strikingly, telomerase overexpression in normal human fibroblasts treated with TNF-alpha strongly repressed ROS-dependent activation of both ERK1/2 mitogen-activated protein kinases and cell death. Telomerase overexpression also considerably diminished TNF-alpha-induced transcription of SOD2 Superoxide Dismutase 2 gene by reducing ROS contribution to SOD2 gene induction, both in normal fibroblasts and in cancer cells. Conversely, telomerase did not impair TNF-alpha-induced transcription of various ROS-insensitive NF-kappa B target genes. These data were in apparent contrast with the striking observation that telomerase overexpression induced strong constitutive nuclear accumulation of NF-kappa Bp65. Accumulated NF-kappa Bp65, however, lacked Ser-536 activating phosphorylation, was not associated with global constitutive NF-kappa B activation and did not impair subsequent nuclear translocation of phosphorylated NF-kappa Bp65 in response to TNF-alpha. Our results demonstrate that human telomerase represses ROS-dependent intracellular signaling and gene induction in response to TNF-alpha.. (C) 2011 Elsevier Inc. All rights reserved.
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