Contact inhibition against senescence

Abstract

Cellular senescence is a form of irreversible growth arrest historically associated with the exhaustion of replicative potential of in vitro cultured cells. Senescence can be triggered by many stimuli, including telomere attrition, DNA damage, oxidative stress, activation of oncogenes, and inactivation of tumor suppressor genes, and plays important roles in tumor suppression, organism aging, tissue repair, and embryonic development [1,2]. One key feature of senescence is irreversibility. Once become arrested, senescent cells cannot be stimulated to proliferate by any known physiological stimuli, despite the availability of space, nutrients and growth factors. This is in contrast to quiescence resulted from growth factor deprivation, which is reversible upon replenishment of the missing growth factors. Another type of quiescence is contact inhibition, in which cells become growth arrested when they contact each other at high density. Similarly contact inhibition is also reversible, as cells re-enter cell cycle and start proliferating when split and re-plated at low density. It had been a mystery what signaling pathways differentiate irreversible senescence from reversible quiescence induced by growth factor deprivation or contact inhibition. Now a recent paper published by Blagosklonny's group demonstrates that the conversion of reversible cell cycle arrest to irreversible senescence, a process termed geroconversion, is governed by the AKT-mammalian target of rapamycin (mTOR) pathway [3]. The AKT/mTOR pathway is an important intracellular growth promoting pathway. Upon activation by receptor tyrosine kinases or G-protein coupled receptors, AKT activates mTOR, which in turn stimulates protein translation through inhibitory phosphorylation of eukaryotic translational initiation factor eIF4E-binding protein 1 (4E-BP1) that inhibits eIF4E, and activating phosphorylation of p70S6 kinase (S6K) that phosphorylates ribosomal S6 protein. A previous study suggests that the status of the mTOR differs between quiescence and senescence [4]. Whereas the phosphorylation of mTOR and its downstream substrates S6K and 4E-BP1 remains high in senescent cells, it is dramatically decreased in cells undergoing serum starvation-induced quiescence. Additional studies indicate that conditions that activate the mTOR pathway convert quiescence to senescence, and that those that inhibit mTOR (such as treatment with the mTOR inhibitor rapamycin and hypoxia) suppress the conversion from quiescence to senescence [4-7]. These studies suggest that the choice between senescence and quiescence is determined, at least in part, by the status of the mTOR pathway. This new study published by the Blagosklonny group focuses on the difference between senescence and quiescence induced by contact inhibition [3]. The author first confirmed that contact inhibition was …

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Cite this paper

@inproceedings{Sun2014ContactIA, title={Contact inhibition against senescence}, author={Peiqing Sun}, booktitle={Oncotarget}, year={2014} }