ArticleProceedings of the National Academy of Sciences of the United States of America2014
Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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107 citing papers in PubMed, 152 citations in OpenAlex.
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- Cell confluency affects p53 dynamics in response to DNA damage.Molecular biology of the cell · 2025Article
- Sustained mTORC1 activation in activated T cells impairs vaccine responses in older individuals.Science advances · 2025Article
- Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.Aging and disease · 2025Review
- Loss of myosin light chain kinase induces the cellular senescence associated secretory phenotype to promote breast epithelial cell migration.Scientific reports · 2024Article
- PQBP3 prevents senescence by suppressing PSME3-mediated proteasomal Lamin B1 degradation.The EMBO journal · 2024Article
- Prostate Cancer's Silent Partners: Fibroblasts and Their Influence on Glutamine Metabolism Manipulation.International journal of molecular sciences · 2024Article
- Early and Late Effects of Low-Dose X-ray Exposure in Human Fibroblasts: DNA Repair Foci, Proliferation, Autophagy, and Senescence.International journal of molecular sciences · 2024Article
- A 3D in vitro model for assessing the influence of intraocular lens: Posterior lens capsule interactions on lens epithelial cell responses.Experimental eye research · 2024Article
- Metabolic symbiosis between oxygenated and hypoxic tumour cells: An agent-based modelling study.PLoS computational biology · 2024Article
- SIRT1 safeguards adipogenic differentiation by orchestrating anti-oxidative responses and suppressing cellular senescence.GeroScience · 2024Article
- Evaluating Chromosome Instability and Genotoxicity Through Single Cell Quantitative Imaging Microscopy.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Genome homeostasis defects drive enlarged cells into senescence.Molecular cell · 2023Article
- Epithelial tissue confinement inhibits cell growth and leads to volume-reducing divisions.Developmental cell · 2023Article
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47 more citing papers are in PubMed but not listed here.
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3 authors at 1 institution in 1 country.
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Abstract
During cell cycle arrest caused by contact inhibition (CI), cells do not undergo senescence, thus resuming proliferation after replating. The mechanism of senescence avoidance during CI is unknown. Recently, it was demonstrated that the senescence program, namely conversion from cell cycle arrest to senescence (i.e., geroconversion), requires mammalian target of rapamycin (mTOR). Geroconversion can be suppressed by serum starvation, rapamycin, and hypoxia, which all inhibit mTOR. Here we demonstrate that CI, as evidenced by p27 induction in normal cells, was associated with inhibition of the mTOR pathway. Furthermore, CI antagonized senescence caused by CDK inhibitors. Stimulation of mTOR in contact-inhibited cells favored senescence. In cancer cells lacking p27 induction and CI, mTOR was still inhibited in confluent culture as a result of conditioning of the medium. This inhibition of mTOR suppressed p21-induced senescence. Also, trapping of malignant cells among contact-inhibited normal cells antagonized p21-induced senescence. Thus, we identified two nonmutually exclusive mechanisms of mTOR inhibition in high cell density: (i) CI associated with p27 induction in normal cells and (ii) conditioning of the medium, especially in cancer cells. Both mechanisms can coincide in various proportions in various cells. Our work explains why CI is reversible and, most importantly, why cells avoid senescence in vivo, given that cells are contact-inhibited in the organism.
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