Role of p53 in the Regulation of Cellular Senescence

Abstract

The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development.Biomolecules 2020, 10, 420 2 of 16 focus on the p53-dependent senescence signaling pathways involved with different stages of senescence and with a consideration for the associated key biomarkers. We also provide an overview on the regulation of p53-mediated cellular senescence in the context of different pathophysiological conditions. Senescence as Cellular Response to StressCellular senescence is defined as a cell state characterized by prolonged and generally irreversible cell-cycle arrest [14] and the acquisition of different phenotypic alterations, including morphological changes, chromatin remodeling, metabolic reprogramming, and secretion of pro-inflammatory factors or SASP (senescence associated secretory phenotypes). These latter count cytokines, growth factors, proteases, and non-soluble extracellular matrix proteins [15]. All these features ultimately limit the replication of both old and damaged cells. Upon physiological conditions, proliferating cells commit to a regular cell cycle [15,16]. On the other hand, both physiological aging, characterized by telomere shortening, and long-term chronic stress, which impairs genomic integrity and stability, could lead to the activation of the senescence pathway [17]. In this sense, the senescence can be viewed as an adaptative response of cells and organisms when exposed to certain unfavorable environmental conditions.Stressors include both intrinsic factors, such as oxidative damage, telomere attrition, hyperproliferation, oncogene activation, and environmental sources, including UV-light, γ-irradiation, and chemotherapeutic drugs [18,19]. Regardless of their origin, the stress factors trigger DNA damage responses (DDR) in the affected cells, which can result in different outcomes, depending on the cell type and the extent of the damage [20]. Mild DNA damage normally induces cell cycle arrest, while severe injury can activate the senescence program or the death programs; the latter includes apoptosis, mitotic catastrophe, autophagy, and necrosis [21].p53 plays a pivotal role in determining the fate of th...

Loss of Dystroglycan Drives Cellular Senescence via Defective Mitosis-Mediated Genomic Instability

“…Supporting the idea that DG deficiency makes the cell more prone to DNA-damage response, upregulation of the p53 pathway (p53 and p21 proteins) was found in DG-KO cells upon thymidine treatment. p53 plays a pivotal role for senescence induction; the DNA damage response activates ataxia telangiectasia (ATM) and Rad3-related (ATR) kinases, which in turn activate the p53/p21 axis by phosphorylation of both p53 and its ubiquitin ligase Mdm2, leading to the stabilization of p53 levels [ 51 ]. However, differences in p53 pathway activation between DG-KO1 and DG-KO2 cells due to inter-clonal heterogeneity cannot be ruled out.…”

Ubiquilin Networking in Cancers

“…Failure of checkpoint mechanism leads to cancer progression and anti-cancer drug resistance [23,24]. The tumor suppressor protein, p53 mediates various mechanisms to arrest cell cycle and allow DNA repairs or induce cell apoptosis due to an occurrence of unmanageable DNA damages [25]. With a wide spectrum of its functions participating in stress response, hypoxia, nutrient deprivation, telomere erosion, UV light, ionized radiation and chemotherapeutic reagents and so forth [26,27], it becomes an essential interactor between extrinsic factors and intrinsic biological responses.…”

A Tryptophan Metabolite, 8-Hydroxyquinaldic Acid, Exerts Antiproliferative and Anti-Migratory Effects on Colorectal Cancer Cells

“…Importantly, it also has a direct impact on genetic differences between tested cell lines. HT-29 cells possess a mutated form of the tumor suppressor p53 gene, involved in genome stability and integrity [22]. In p53-mutated cells, p21 Waf1/Cip1 plays a crucial role in the induction of cell cycle arrest and apoptosis.…”

“…However, loss of anti-migratory potential of 1 mM 8-hydroxyquinaldic acid in HT-29 cells might be induced by nuclear translocation of this protein indicated by immunofluorescent staining (Figure 8). It should be underlined that several various signaling pathways (i.e., MAPK, PI3K/Akt signaling pathways), transcription factors (i.e.,TWIST1, Snail, Slug, ZEB1/2), and cytokines (i.e., VEGF, TGFβ) may be involved in the migration and invasiveness of cancer cells [22]. Thus, it cannot be excluded that anti-migratory activity of 8-hydroxyquialdic acid towards colon cancer HT-29 and LS-180 cells may not only be dependent on cadherin and β-catenin expression, but affect other elements involved in this process.…”