Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/12946
Título
Early induction of senescence and immortalization in PGC-1α-deficient mouse embryonic fibroblasts
Autor(es)
Prieto, Ignacio | Zambrano, Alberto ISCIII | Laso, Javier | Aranda, Ana | Samper, Enrique CNIC | Monsalve, María
Fecha de publicación
2019
Cita
Free Radic Biol Med. 2019 Jul;138:23-32.
Idioma
Inglés
Tipo de documento
journal article
Resumen
Oxidative stress is known to induce early replicative senescence. Senescence has been proposed to work as a barrier to immortalization and tumor development. Here, we aimed to evaluate the impact of the loss of peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α), a master regulator of oxidative metabolism and mitochondrial reactive oxygen species (ROS) generation, on replicative senescence and immortalization in mouse embryonic fibroblasts (MEFs).
We found that primary MEFs lacking PGC-1α showed higher levels of ROS than wild-type MEFs at all cell passages tested. The elevated production of ROS was associated with higher levels of oxidative DNA damage and the increased formation of DNA double-strand breaks. Evaluation of the induction of DNA repair systems in response to γ-radiation indicated that the loss of PGC-1α also resulted in a small but significant reduction in their activity. DNA damage induced the early activation of senescence markers, including an increase in the number of β-galactosidase-positive cells, the induction of p53 phosphorylation, and the increase in p16 and p19 protein. These changes were, however, not sufficient to reduce proliferation rates of PGC-1α-deficient MEFs at any cell passage tested. Moreover, PGC-1α-deficient cells escaped replicative senescence.
PGC-1α plays an important role in the control of cellular senescence and immortalization.
Palabras clave
MESH
DNA Repair | Animals | Biomarkers | Cell Proliferation | Cellular Senescence | Cyclin-Dependent Kinase Inhibitor p16 | Cyclin-Dependent Kinase Inhibitor p19 | DNA | DNA Breaks, Double-Stranded | Embryo, Mammalian | Fibroblasts | Gamma Rays | Gene Expression Regulation | Mice | Mice, Knockout | Mitochondria | Oxidative Stress | Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha | Phosphorylation | Reactive Oxygen Species | Tumor Suppressor Protein p53 | Beta-Galactosidase
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