2024-03-29T09:12:46Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1887502022-05-05T07:43:12Zcom_10261_22com_10261_1col_10261_275
Prieto, Ignacio
Zambrano, Alberto
Laso, Javier
Aranda, Ana
Samper, Enrique
Monsalve, María
2019-08-21T11:54:39Z
2019-08-21T11:54:39Z
2019
Free Radical Biology and Medicine 138: 23-32 (2019)
0891-5849
http://hdl.handle.net/10261/188750
10.1016/j.freeradbiomed.2019.04.015
1873-4596
http://dx.doi.org/10.13039/501100000780
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/501100010198
http://dx.doi.org/10.13039/501100003329
31029787
[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.
eng
openAccess
Early induction of senescence and immortalization in PGC-1α-deficient mouse embryonic fibroblasts
artículo