Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program

Proceedings of the National Academy of Sciences of the United States of America

Volumn 111, Issue 24, 2014, Pages 8832-8837

  Leontieva, Olga V ^a   Demidenko, Zoya N ^a   Blagosklonny, Mikhail V ^a  

^a ROSWELL PARK CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; MAMMALIAN TARGET OF RAPAMYCIN; PALBOCICLIB; PROTEIN P21; PROTEIN P27;

ARTICLE; CANCER CELL; CELL CYCLE ARREST; CELL DENSITY; CELL METABOLISM; CELL PROLIFERATION; CONTACT INHIBITION; CONTROLLED STUDY; FIBROSARCOMA CELL LINE; FLOW CYTOMETRY; HUMAN; HUMAN CELL; IMMUNOBLOTTING; PIGMENT EPITHELIUM; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; SENESCENCE;

BETA-GALACTOSIDASE; CELL AGING; CELL CYCLE; CELL CYCLE CHECKPOINTS; CELL LINE, TUMOR; CELL PROLIFERATION; CONTACT INHIBITION; CULTURE MEDIA, CONDITIONED; CYCLIN-DEPENDENT KINASE INHIBITOR P21; CYCLIN-DEPENDENT KINASE INHIBITOR P27; FIBROSARCOMA; FLOW CYTOMETRY; HUMANS; NEOPLASMS; RETINAL PIGMENT EPITHELIUM; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84902578762     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1405723111     Document Type: Article

References (54)

1. Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88(5):593-602. (Pubitemid 27152402)
2. Ferbeyre G, et al. (2002) Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol 22(10):3497-3508. (Pubitemid 34453988)
3. Blagosklonny MV (2003) Cell senescence and hypermitogenic arrest. EMBO Rep 4(4): 358-362.
4. Deng Q, Liao R, Wu BL, Sun P (2004) High intensity ras signaling induces premature senescence by activating p38 pathway in primary human fibroblasts. J Biol Chem 279(2):1050-1059. (Pubitemid 38082626)
5. Demidenko ZN, Blagosklonny MV (2008) Growth stimulation leads to cellular senescence when the cell cycle is blocked. Cell Cycle 7(21):3355-3361.
6. Demidenko ZN, Korotchkina LG, Gudkov AV, Blagosklonny MV (2010) Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci USA 107(21):9660-9664.
7. Leontieva OV, et al. (2012) Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Proc Natl Acad Sci USA 109(33):13314-13318.
8. Cho S, Hwang ES (2012) Status of mTOR activity may phenotypically differentiate senescence and quiescence. Mol Cells 33(6):597-604.
9. Kolesnichenko M, Hong L, Liao R, Vogt PK, Sun P (2012) Attenuation of TORC1 signaling delays replicative and oncogenic RAS-induced senescence. Cell Cycle 11(12): 2391-2401.
10. Leontieva OV, Demidenko ZN, Blagosklonny MV (2013) MEK drives cyclin D1 hyper-elevation during geroconversion. Cell Death Differ 20(9):1241-1249.
11. Serrano M (2012) Dissecting the role of mTOR complexes in cellular senescence. Cell Cycle 11(12):2231-2232.
12. Blagosklonny MV (2012) Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: Terminology for TOR-driven aging. Aging (Albany, NY Online) 4(3):159-165.
13. Dulic V (2013) Senescence regulation by mTOR. Methods Mol Biol 965:15-35.
14. Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20(3): 267-275. (Pubitemid 43200281)
15. Feng Z, Levine AJ (2010) The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol 20(7):427-434.
16. Abercrombie M (1979) Contact inhibition and malignancy. Nature 281(5729):259-262.
17. Lloyd RV, et al. (1999) p27kip1: A multifunctional cyclin-dependent kinase inhibitor with prognostic significance in human cancers. Am J Pathol 154(2):313-323. (Pubitemid 29094081)
18. Leontieva OV, Blagosklonny MV (2011) Yeast-like chronological senescence in mammalian cells: Phenomenon, mechanism and pharmacological suppression. Aging (Albany, NY Online) 3(11):1078- 1091.
19. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging. Proc Natl Acad Sci USA 98(21):12072-12077. (Pubitemid 32959828)
20. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123(3):966-972.
21. Pani G (2011) From growing to secreting: new roles for mTOR in aging cells. Cell Cycle 10(15):2450-2453.
22. Knecht E, Hernández-Yago J, Grisolía S (1984) Regulation of lysosomal autophagy in transformed and non-transformed mouse fibroblasts under several growth conditions. Exp Cell Res 154(1):224-232. (Pubitemid 14006423)
23. Severino J, Allen RG, Balin S, Balin A, Cristofalo VJ (2000) Is beta-galactosidase staining a marker of senescence in vitro and in vivo? Exp Cell Res 257(1):162-171. (Pubitemid 30324654)
24. Kurz DJ, Decary S, Hong Y, Erusalimsky JD (2000) Senescence-associated (beta)- galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113(pt 20):3613 -3622.
25. Yang NC, Hu ML (2005) The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol 40(10):813-819.
26. Gary RK, Kindell SM (2005) Quantitative assay of senescence-associated beta-galactosidase activity in mammalian cell extracts. Anal Biochem 343(2):329- 334.
27. Coates PJ (2002) Markers of senescence? J Pathol 196(4):371-373.
28. Krishna DR, Sperker B, Fritz P, Klotz U (1999) Does pH 6 beta-galactosidase activity indicate cell senescence? Mech Ageing Dev 109(2):113-123. (Pubitemid 29397514)
29. Yegorov YE, Akimov SS, Hass R, Zelenin AV, Prudovsky IA (1998) Endogenous beta-galactosidase activity in continuously nonproliferating cells. Exp Cell Res 243(1):207-211. (Pubitemid 28397649)
30. Papadopoulos T, Pfeifer U (1987) Protein turnover and cellular autophagy in growing and growth-inhibited 3T3 cells. Exp Cell Res 171(1):110-121. (Pubitemid 18089658)
31. Lee BY, et al. (2006) Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell 5(2):187- 195.
32. Dimri GP, et al. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92(20):9363-9367.
33. Blagosklonny MV (2013) Hypoxia, MTOR and autophagy: Converging on senescence or quiescence. Autophagy 9(2):260-262.
34. Chassot AA, et al. (2008) Confluence-induced cell cycle exit involves pre-mitotic CDK inhibition by p27(Kip1) and cyclin D1 downregulation. Cell Cycle 7(13):2038-2046.
35. Groth A, Willumsen BM (2005) High-density growth arrest in Ras-transformed cells: Low Cdk kinase activities in spite of absence of p27(Kip) Cdk-complexes. Cell Signal 17(9):1063-1073. (Pubitemid 40933527)
36. Nakayama K, et al. (1996) Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85(5):707-720.
37. Levenberg S, Yarden A, Kam Z, Geiger B (1999) p27 is involved in N-cadherin-mediated contact inhibition of cell growth and S-phase entry. Oncogene 18(4):869-876. (Pubitemid 29086263)
38. Polyak K, et al. (1994) p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev 8(1):9-22.
39. Seluanov A, et al. (2009) Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc Natl Acad Sci USA 106(46):19352-19357.
40. Dietrich C, Wallenfang K, Oesch F, Wieser R (1997) Differences in the mechanisms of growth control in contact-inhibited and serum-deprived human fibroblasts. Oncogene 15(22):2743-2747. (Pubitemid 27507622)
41. Korotchkina LG, et al. (2010) The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging (Albany, NY Online) 2(6):344-352.
42. Leontieva OV, Blagosklonny MV (2012) Hypoxia and gerosuppression: The mTOR saga continues. Cell Cycle 11(21):3926-3931.
43. Broude EV, et al. (2007) p21(Waf1/Cip1/Sdi1) mediates retinoblastoma protein degradation. Oncogene 26(48):6954-6958. (Pubitemid 47609081)
44. Chang BD, et al. (2000) p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19(17):2165-2170.
45. Demidenko ZN, et al. (2009) Rapamycin decelerates cellular senescence. Cell Cycle 8(12):1888-1895.
46. Leontieva OV, Blagosklonny MV (2013) CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: Duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle 12(18):3063-3069.
47. Leontieva OV, Blagosklonny MV (2010) DNA damaging agents and p53 do not cause senescence in quiescent cells, while consecutive re-activation of mTOR is associated with conversion to senescence. Aging (Albany, NY Online) 2(12):924-935.
48. Leontieva OV, Lenzo F, Demidenko ZN, Blagosklonny MV (2012) Hyper-mitogenic drive coexists with mitotic incompetence in senescent cells. Cell Cycle 11(24):4642-4649.
49. Mercier I, et al. (2012) Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and antiaging drug. Am J Pathol 181(1):278-293.
50. Iglesias-Bartolome R, et al. (2012) mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell 11(3):401-414.
51. Iglesias-Bartolome R, Gutkind SJ (2012) Exploiting the mTOR paradox for disease prevention. Oncotarget 3(10):1061-1063.
52. Hinojosa CA, et al. (2012) Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence. Exp Gerontol 47(12):958-965.
53. Luo Y, et al. (2014) Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence. Transplantation 97(1):20-29.
54. Leontieva OV, et al. (2013) Dysregulation of the mTOR pathway in p53-deficient mice. Cancer Biol Ther 14(12):1182-1188.