Abstract
SummaryCellular senescence has been implicated in normal aging, tissue homeostasis, and tumor suppression. Although p53 has been shown to be a central mediator of cellular senescence, the signaling pathway by which it induces senescence remains incompletely understood. In this study, we have shown that both Akt and p21 are required to induce cellular senescence in response to p53 expression. In a p53‐induced senescence model, we found that Akt activation was essential for inducing a cellular senescence phenotype. Surprisingly, Akt inhibition did not abolish p53‐induced cell cycle arrest, but it suppressed the increase in intracellular reactive oxygen species (ROS) levels. The results of the cell cycle and morphological analysis suggest that p53 induced quiescence, not senescence, following Akt inhibition. Conversely, the inhibition of p21 induction abolished cell cycle arrest but did not affect the p53‐induced increase in ROS levels. Additionally, p21 and Akt separately controlled cell cycle arrest and ROS levels, respectively, during H‐Ras‐induced senescence in human normal fibroblasts. The mechanistic analysis revealed that Akt increased ROS levels through NOX4 induction, and increased Akt‐dependent NF‐κB binding to the NOX4 promoter is responsible for NOX4 induction upon p53 expression. We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2. In addition, p53‐mediated IL6 and IL8 induction was abrogated by Akt inhibition, suggesting that Akt activation is also required for the senescence‐associated secretory phenotype. Collectively, these results suggest that p53 simultaneously controls multiple pathways to induce cellular senescence through p21 and Akt.
Highlights
Cellular senescence was first described by Hayflick et al as the limited proliferative capacity of normal human fibroblasts
Irreversible growth arrest, which is characteristic of cellular senescence, was confirmed by a marked reduction in cell growth and decreased number of cells in the S-phase upon p53 expression (Fig. S1A,B)
Extensive molecular analysis revealed that the levels of Akt phosphoSer473 and phospho-Thr308, which are both indicators of Akt activation, were strongly increased 2 days after the induction of p53 expression, whereas the Akt protein level remained the same (Fig. 1B)
Summary
Cellular senescence was first described by Hayflick et al as the limited proliferative capacity of normal human fibroblasts. While this phenomenon, termed ‘replicative senescence’, is known to contribute to Accepted for publication 4 June 2017 organismal aging processes, another type of cellular senescence, termed ‘premature senescence’ or ‘stress-induced senescence’, is considered a barrier to tumorigenesis because it acts to remove precancerous cells (Collado et al, 2005; Collado & Serrano, 2010). Extensive previous studies have shed light on the essential role of the tumor suppressor p53 in the induction and maintenance of cellular senescence (Kuilman et al, 2010; Rufini et al, 2013). With regard to replicative senescence, p53 activation by the DNA damage signaling cascade in response to telomere erosion is considered a critical step in the induction of cellular senescence (Kuilman et al, 2010). p53 has been shown to play pivotal roles in various premature senescence models, such as anticancer drug- and H-Ras oncogene-induced senescence (OIS) (Ferbeyre et al, 2002)
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