Cell senescence: Hypertrophic arrest beyond the restriction point

Abstract

Withdrawal of mitogens (growth factors) arrests normal cells in G0 (quiescence). All other stresses and factors arrest cell cycle beyond the restriction point in G1 and G2 (non-G0 arrest), in the presence of mitogenic stimulation. Strong mitogenic stimuli by themselves cause non-G0 arrest. Unlike G0, arrest beyond restriction point is characterized by both high levels of cyclins and CDK inhibitors, activated mitogenic pathways with a secondary GF resistance, and continuous mass growth (cell hypertrophy). Prolonged hypertrophic arrest culminates in cell senescence. This review discusses that quiescence and senescence are two opposite, mutually exclusive conditions and that cell senescence can be reversed and prevented.

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

“…This finding is in line with the observation that elevated cytosolic levels of phosphorylated ERK1/2 are required for Ras-induced senescence (Gaumont-Leclerc et al, 2004), whereas nucleartargeted ERK1/2 delays the onset of senescence (Tresini et al, 2007). Retention of phospho-ERK1/2 in the cytoplasm might promote senescence through attenuating the phosphorylation of nuclear ERK targets, thus explaining why increased ERK activation is associated with induction of senescence (Blagosklonny, 2006a;Cagnol and Chambard, 2009). Recent studies using time-lapse microscopy have revealed profound intra-and interline variations of cancer cell lines in their response to antimitotic drugs (Gascoigne and Taylor, 2008;Shi et al, 2008).…”

“…As an alternative to apoptosis, cells can undergo permanent cell cycle arrest by cellular senescence, which is typically characterized by growth arrest, apoptosis resistance and altered gene expression (Campisi and d'Adda di Fagagna, 2007). Cellular senescence can be either triggered through telomere shortening (intrinsic or replicative senescence) or initiated by various stress stimuli, for example, DNA damage, oxidative stress or oncogene activation (extrinsic or stress-induced premature senescence (SIPS)) (Roninson et al, 2001;Ben-Porath and Weinberg, 2005;Blagosklonny, 2006a). Although cells undergoing replicative or premature senescence are metabolically active, they are unable to synthesize DNA even in response to growth factors.…”

p21Waf1is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate

“…Senescent cells manifest the increased cell size and spread over a substrate; these events being considered as specific markers of senescent cells 21 or triggers of cellular senescence. 19,20 In fact, long-term treatment of Waf1 +/+ cells leads to an increase of the cell size ( Fig. 2A and B).…”

“…17 Taken together, these data serve as evidence that accumulation of senescence-associated γH2AX foci can be a trigger of hyperactivation of pathways involved in cell senescence, as was recently proposed on a mouse model, 18 or its consequence. 9,19 Thus, although HDACI exert antiproliferative effect due in part to activation of the p21 Waf1 gene transcription, 5 nevertheless, p21…”

p53 Protein-mediated Up-regulation of MAP Kinase Phosphatase 3 (MKP-3) Contributes to the Establishment of the Cellular Senescent Phenotype through Dephosphorylation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2)

“…Activated CDKs phosphorylate retinoblastoma protein and prevent the formation of the E2F complex, therefore promoting progression of the cell cycle from G 1 phase to S phase (10). In senescent cells, the cell cycle inhibitors p53/ p21…”