The odyssey of telomerase in regulating cellular responses to cytokines and reactive oxygen species
Year: 2011
Type: dissertation
Abstract: During the multistep tumorigenic process, cancer cells progressively acquire properties that include an unlimited replicative potential, invasion, sustained proliferative signaling, metastasis and resistance to cell death. In addition to its well-established role in telomere synthesis, telomerase was reported to exert non-canonical functions that may promote several abilities of cancer cells, notably by lowering reactive oxygen species (ROS) levels, modulating chromatin properties and acting as transcriptional cofactor in Wnt/β-catenin signaling pathway.\nThe aim of this thesis was to investigate possible non-canonical functions of telomerase in regulating human fibroblasts responses to cytokines, namely Tumor Necrosis Factor-α (TNF-α) pro-inflammatory cytokine and Transforming Growth Factor-β1 (TGF-β1). \nROS have been involved in a variety of cellular events downstream of TNF-α binding to its receptor, including mitogen-activated protein kinase (MAPK) activation, apoptosis and induction of some -but not all- NF-κB target genes. The previously reported antioxidant properties of telomerase prompted us to test whether telomerase may be able to modulate ROS-dependent and/or -independent cellular responses to TNF-α, a potent inducer of NF-κB pathway. We showed that telomerase overexpression in normal human fibroblasts, strongly repress activation of ERK1/2 mitogen-activated protein kinases and cell death. In contrast, telomerase overexpression did not affect ROS-independent cellular responses to TNF-α, including NF-κB activation, nuclear translocation of phosphorylated NF-κBp65 and TNF-α-induced transcription of various NF-κB target genes. However, telomerase expression considerably repressed TNF-α-induced transcription of the ROS-sensitive NF-κB target gene SOD2 by reducing ROS contribution to SOD2 gene induction, both in normal fibroblasts and in cancer cells. Our results demonstrate that human telomerase represses ROS-dependent intracellular signaling and gene induction in response to TNF-α without affecting NF-κB activation. \nPrevious studies suggested a possible regulatory role of mouse telomerase on TGF-β signaling pathway. The second aim of this thesis was to investigate whether human telomerase may modulate cellular responses to TGF-β1. We showed that telomerase overexpression in human foreskin fibroblasts does not globally impact on TGF-β signaling as shown by unaltered activation of Smad regulators and similar induction of TGF-β1-target genes. However, telomerase strongly and significantly increased induction of JUNB proto-oncogene transcription in different fibroblast cell lines in response to TGF-β1 treatment. Additional experiments are required to elucidate how human telomerase increase JUNB induction in response to TGF-β1.\nIn summary, our work provides the first evidences for a role of human telomerase in ROS-dependent transcriptional regulation and MAPK activation and further supports the existence of antioxidant functions of telomerase in mitochondria.
Author: Marina Mattiussi
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1752010110