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Early induction of senescence and immortalization in PGC-1α-deficient mouse embryonic fibroblasts

AuthorsPrieto, Ignacio; Zambrano, Alberto ; Laso, Javier; Aranda, Ana ; Samper, Enrique; Monsalve, María
Issue Date2019
CitationFree Radical Biology and Medicine 138: 23-32 (2019)
Abstract[Aims]: 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).
[Results]: 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.
[Innovation & conclusion]: PGC-1α plays an important role in the control of cellular senescence and immortalization.
Publisher version (URL)https://doi.org/10.1016/j.freeradbiomed.2019.04.015
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