Abstract
When the cell cycle is arrested, growth-promoting pathways such as mTOR (Target of Rapamycin) drive cellular senescence, characterized by cellular hyper-activation, hypertrophy and permanent loss of the proliferative potential. While arresting cell cycle, p53 (under certain conditions) can inhibit the mTOR pathway. Senescence occurs when p53 fails to inhibit mTOR. Low concentrations of DNA-damaging drugs induce p53 at levels that do not inhibit mTOR, thus causing senescence. In quiescence caused by serum starvation, mTOR is deactivated. This predicts that induction of p53 will not cause senescence in such quiescent cells. Here we tested this prediction. In proliferating normal cells, etoposide caused senescence (cells could not resume proliferation after removal of etoposide). Serum starvation prevented induction of senescence, but not of p53, by etoposide. When etoposide was removed, such cells resumed proliferation upon addition of serum. Also, doxorubicin did not cause senescent morphology in the absence of serum. Re-addition of serum caused mTOR-dependent senescence in the presence of etoposide or doxorubicin. Also, serum-starvation prevented senescent morphology caused by nutlin-3a in MCF-7 and Mel-10 cells. We conclude that induction of p53 does not activate the senescence program in quiescent cells. In cells with induced p53, re-activation of mTOR by serum stimulation causes senescence, as an equivalent of cellular growth.
Highlights
Serum growth factors (GF) activate the GF-sensing network, which turns on both cell cycle progression and the mTOR pathway, which in turn stimulates cellular growth in size [1,2,3,4,5]
Cellular senescence is characterized by cellular hypertrophy, hypersecretory phenotype, beta-Gal-staining and permanent loss of proliferative potential [6,7,8]
Cells were treated with nutlin-3a and etoposide in the presence of rapamycin (Figure 1B)
Summary
Serum growth factors (GF) activate the GF-sensing network, which turns on both cell cycle progression and the mTOR pathway, which in turn stimulates cellular growth in size [1,2,3,4,5]. Cells progress through the cell cycle and divide. Serum withdrawal both arrests the cell cycle early in G1, known as G0 and deactivates mTOR. Cells become quiescent: they neither grow in size nor progress through the cell cycle. Cellular senescence is not caused by serum GF withdrawal, but by stresses and oncogenic/mitogenic hyper-stimulation [9,10,11,12,13,14,15]. While not inhibiting mTOR, these stimuli incite responses blocking cell cycle
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call