Growth stimulation leads to cellular senescence when the cell cycle is blocked

Abstract

We tested a hypothesis that activation of growth-promoting pathways is required for cellular senescence. In the presence of serum, induction of p21 caused senescence, characterized by betaGalactosidase staining, cell hypertrophy, increased levels of cyclin D1 and active TOR (target of rapamycin, also known as mTOR). Serum starvation and rapamycin inhibited TOR and prevented the expression of some senescent markers, despite high levels of p21 and cell cycle arrest. In the presence of serum, p21-arrested cells irreversibly lost proliferative potential. In contrast, when cells were arrested by p21 in the absence of serum, they retained the capacity to resume proliferation upon termination of p21 induction. In normal human cells such as WI38 fibroblasts and retinal pigment epithelial (RPE) cells, serum starvation caused quiescence, which was associated with low levels of cyclin D1, inactive TOR and slim-cell morphology. In contrast, cellular senescence with high levels of TOR activity was induced by doxorubicin (DOX), a DNA damaging agent, in the presence of serum. Inhibition of TOR partially prevented senescent phenotype caused by DOX. Thus growth stimulation coupled with cell cycle arrest leads to senescence, whereas quiescence (a condition with inactive TOR) prevents senescence.

p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

“…This is consistent with doxorubicin-induced senescence in tumor cells (Chang et al, 1999) and primary fibroblasts (Baus et al, 2003;Demidenko and Blagosklonny, 2008).…”

Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

“…Interestingly, similar finding occurred in HDF cells at 5 days, but in Huh7 cancer cells at 3 days, after treatment with H 2 O 2 . The more rapid response to actin regulating phenomenon in cancer cells may be accounted for by the fact that the more actively growing cells can reach cellular senescence earlier than that of the growth arrested cells [6]. Indeed, infection of retrovirus carrying H-ras double mutants can induce premature senescence of primary culture of HDF, compared with HDF cells infected with the control virus [7,8].…”

“…Cellular senescence is accelerated by DNA damage and stresses, i.e. induced senescence, whereas inhibition of cell growth prevents cellular senescence when the cell cycle is blocked by DNA damage and p21 WAF1 [6]. We earlier reported that globular actin (G-actin) accumulates in nuclei of the replicatively senescent human diploid E X P E R I M E N T A L C E L L R E S E A R C H 3 1 7 ( 2 0 1 1 ) 9 4 1 -9 5 4 fibroblasts (HDF) and induced senescence of cancer cells by treatment with either H 2 O 2 , deferoxamine, TGF-β1 or over expression of H-Ras double mutants [7][8][9].…”

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

“…[7][8][9][10][11][12] Recently these pathways have been shown to play critical roles in the preventing aging and senescence. [12][13][14][15][16] Thus these pathways have been targeted to promote longevity by altering the aging process which might be enhanced when these pathways are hyperactivated. these pathways is mediated by a series of kinases, phosphatases and various exchange proteins.…”