Biopolym. Cell. 2015; 31(5):323-337.
http://dx.doi.org/10.7124/bc.0008F4
Огляди
Особливості молекулярних механізмів передчасного клітинного старіння, які залежать від стрес-фактору, що індукує старіння
1Петрова Надєжда В., 1Величко Артем К., 1Петрова Наталія В., 1, 2Разін Сергій В., 1Кантидзе Омар Л.
  1. Інститут біології гена РАН
    вул. Вавілова 34/5, Москва, Російська Федерація, 119334
  2. Московський державний університет імені М. В. Ломоносова
    Ленінські гори, 1/12, Москва, Російська Федерація, 119991

Abstract

Клітинне старіння є відповіддю клітини на стрес у вигляді перманентного арешту проліферації, супроводжуваного комплексом фенотипічних змін. Найбільш важливими ознаками клітинного старіння є відсутність синтезу ДНК, збільшення активності асоційованої зі старінням β-галактозидази і збільшення експресії інгібіторів циклин-залежних кіназ. Ці універсальні маркери клітинного старіння характерні також і для інших типів арешту проліферації клітин. Поряд з універсальними маркерами клітинне старіння має додаткові характеристики, які більшою мірою залежать від фактора, що індукує старіння та / або типу клітин. У цьому огляді ми розглянемо основні характеристики і механізми, індукції клітинного старіння, приділивши особливу уваги залежних від стрес-фактора відмінностям активуються при клітинному старінні сигнальних каскадів.
Keywords: клітинне старіння, теломери, пошкодження ДНК, опромінення, активні форми кисню, онкогени
Повний текст: (PDF, англійською)

References

[1] Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585-621.
[2] Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614-36.
[3] Olovnikov AM. [Principle of marginotomy in template synthesis of polynucleotides]. Dokl Akad Nauk SSSR. 1971;201(6):1496-9.
[4] Watson JD. Origin of concatemeric T7 DNA. Nat New Biol. 1972;239(94):197-201.
[5] Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345(6274):458-60.
[6] Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279(5349):349-52.
[7] Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005;37(5):961-76.
[8] Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705.
[9] Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24(22):2463-79.
[10] Robbins E, Levine EM, Eagle H. Morphologic changes accompanying senescence of cultured human diploid cells. J Exp Med. 1970;131(6):1211-22.
[11] Greenberg SB, Grove GL, Cristofalo VJ. Cell size in aging monolayer cultures. In Vitro. 1977;13(5):297-300.
[12] Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995;92(20):9363-7.
[13] Kurz DJ, Decary S, Hong Y, Erusalimsky JD. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci. 2000;113 ( Pt 20):3613-22.
[14] Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, Kleijer WJ, DiMaio D, Hwang ES. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5(2):187-95.
[15] Michaloglou C, Soengas MS, Mooi WJ, Peeper DS. Comment on "Absence of senescence-associated beta-galactosidase activity in human melanocytic nevi in vivo". J Invest Dermatol. 2008;128(6):1582-3.
[16] Campisi J, d'Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729-40.
[17] Fang L, Igarashi M, Leung J, Sugrue MM, Lee SW, Aaronson SA. p21Waf1/Cip1/Sdi1 induces permanent growth arrest with markers of replicative senescence in human tumor cells lacking functional p53. Oncogene. 1999;18(18):2789-97.
[18] Malumbres M, Pérez De Castro I, Hernández MI, Jiménez M, Corral T, Pellicer A. Cellular response to oncogenic ras involves induction of the Cdk4 and Cdk6 inhibitor p15(INK4b). Mol Cell Biol. 2000;20(8):2915-25.
[19] Tsugu A, Sakai K, Dirks PB, Jung S, Weksberg R, Fei YL, Mondal S, Ivanchuk S, Ackerley C, Hamel PA, Rutka JT. Expression of p57(KIP2) potently blocks the growth of human astrocytomas and induces cell senescence. Am J Pathol. 2000;157(3):919-32.
[20] Munro J, Steeghs K, Morrison V, Ireland H, Parkinson EK. Human fibroblast replicative senescence can occur in the absence of extensive cell division and short telomeres. Oncogene. 2001;20(27):3541-52.
[21] d'Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8(7):512-22.
[22] Lukas C, Savic V, Bekker-Jensen S, Doil C, Neumann B, Pedersen RS, Grøfte M, Chan KL, Hickson ID, Bartek J, Lukas J. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat Cell Biol. 2011;13(3):243-53.
[23] Wang Q, Goldstein M, Alexander P, Wakeman TP, Sun T, Feng J, Lou Z, Kastan MB, Wang XF. Rad17 recruits the MRE11-RAD50-NBS1 complex to regulate the cellular response to DNA double-strand breaks. EMBO J. 2014;33(8):862-77.
[24] Narita M, Nũnez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113(6):703-16.
[25] Narita M, Narita M, Krizhanovsky V, Nuñez S, Chicas A, Hearn SA, Myers MP, Lowe SW. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell. 2006;126(3):503-14.
[26] Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell. 2005;8(1):19-30.
[27] Chandra T, Ewels PA, Schoenfelder S, Furlan-Magaril M, Wingett SW, Kirschner K, Thuret JY, Andrews S, Fraser P, Reik W. Global reorganization of the nuclear landscape in senescent cells. Cell Rep. 2015;10(4):471-83.
[28] Kosar M, Bartkova J, Hubackova S, Hodny Z, Lukas J, Bartek J. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle. 2011;10(3):457-68.
[29] Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.
[30] Pérez-Mancera PA, Young AR, Narita M. Inside and out: the activities of senescence in cancer. Nat Rev Cancer. 2014;14(8):547-58.
[31] Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973-9.
[32] Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536-48.
[33] Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson-Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015;17(8):1049-61.
[34] Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, Takatsu Y, Melamed J, d’Adda di Fagagna F, Bernard D, Hernando E, Gil J. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18.
[35] Lafferty-Whyte K, Cairney CJ, Jamieson NB, Oien KA, Keith WN. Pathway analysis of senescence-associated miRNA targets reveals common processes to different senescence induction mechanisms. Biochim Biophys Acta. 2009;1792(4):341-52.
[36] Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci. 2012;125(Pt 1):7-17.
[37] Zhao T, Li J, Chen AF. MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. Am J Physiol Endocrinol Metab. 2010;299(1):E110-6.
[38] Li N, Muthusamy S, Liang R, Sarojini H, Wang E. Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1. Mech Ageing Dev. 2011;132(3):75-85.
[39] Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A. 2007;104(39):15472-7.
[40] Kumamoto K, Spillare EA, Fujita K, Horikawa I, Yamashita T, Appella E, Nagashima M, Takenoshita S, Yokota J, Harris CC. Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res. 2008;68(9):3193-203.
[41] Ugalde AP, Ramsay AJ, de la Rosa J, Varela I, Mariño G, Cadiñanos J, Lu J, Freije JM, López-Otín C. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J. 2011;30(11):2219-32.
[42] Wagner W, Horn P, Castoldi M, Diehlmann A, Bork S, Saffrich R, Benes V, Blake J, Pfister S, Eckstein V, Ho AD. Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS One. 2008;3(5):e2213.
[43] Martinez I, Cazalla D, Almstead LL, Steitz JA, DiMaio D. miR-29 and miR-30 regulate B-Myb expression during cellular senescence. Proc Natl Acad Sci U S A. 2011;108(2):522-7.
[44] Bhaumik D, Scott GK, Schokrpur S, Patil CK, Orjalo AV, Rodier F, Lithgow GJ, Campisi J. MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging (Albany NY). 2009;1(4):402-11.
[45] Li G, Luna C, Qiu J, Epstein DL, Gonzalez P. Modulation of inflammatory markers by miR-146a during replicative senescence in trabecular meshwork cells. Invest Ophthalmol Vis Sci. 2010;51(6):2976-85.
[46] Bonifacio LN, Jarstfer MB. MiRNA profile associated with replicative senescence, extended cell culture, and ectopic telomerase expression in human foreskin fibroblasts. PLoS One. 2010;5(9). pii: e12519.
[47] He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447(7148):1130-4.
[48] Ofir M, Hacohen D, Ginsberg D. MiR-15 and miR-16 are direct transcriptional targets of E2F1 that limit E2F-induced proliferation by targeting cyclin E. Mol Cancer Res. 2011;9(4):440-7.
[49] Puvvula PK, Desetty RD, Pineau P, Marchio A, Moon A, Dejean A, Bischof O. Long noncoding RNA PANDA and scaffold-attachment-factor SAFA control senescence entry and exit. Nat Commun. 2014;5:5323.
[50] Benanti JA, Williams DK, Robinson KL, Ozer HL, Galloway DA. Induction of extracellular matrix-remodeling genes by the senescence-associated protein APA-1. Mol Cell Biol. 2002;22(21):7385-97.
[51] Yang KE, Kwon J, Rhim JH, Choi JS, Kim SI, Lee SH, Park J, Jang IS. Differential expression of extracellular matrix proteins in senescent and young human fibroblasts: a comparative proteomics and microarray study. Mol Cells. 2011;32(1):99-106.
[52] Kaneko S, Satoh Y, Ikemura K, Konishi T, Ohji T, Karasaki Y, Higashi K, Gotoh S. Alterations of expression of the cytoskeleton after immortalization of human fibroblasts. Cell Struct Funct. 1995;20(1):107-15.
[53] Maya-Mendoza A, Merchut-Maya JM, Bartkova J, Bartek J, Streuli CH, Jackson DA. Immortalised breast epithelia survive prolonged DNA replication stress and return to cycle from a senescent-like state. Cell Death Dis. 2014;5:e1351.
[54] Robles SJ, Adami GR. Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts. Oncogene. 1998;16(9):1113-23.
[55] Palaniyappan A. Cyclophosphamide induces premature senescence in normal human fibroblasts by activating MAP kinases. Biogerontology. 2009;10(6):677-82.
[56] Shimi T, Butin-Israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA, Shumaker DK, Kosak ST, Chandel NS, Goldman RD. The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev. 2011;25(24):2579-93.
[57] Freund A, Laberge RM, Demaria M, Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. 2012;23(11):2066-75.
[58] Bridger JM, Boyle S, Kill IR, Bickmore WA. Re-modelling of nuclear architecture in quiescent and senescent human fibroblasts. Curr Biol. 2000;10(3):149-52.
[59] Kar B, Liu B, Zhou Z, Lam YW. Quantitative nucleolar proteomics reveals nuclear re-organization during stress- induced senescence in mouse fibroblast. BMC Cell Biol. 2011;12:33.
[60] Belancio VP, Roy-Engel AM, Pochampally RR, Deininger P. Somatic expression of LINE-1 elements in human tissues. Nucleic Acids Res. 2010;38(12):3909-22.
[61] De Cecco M, Criscione SW, Peterson AL, Neretti N, Sedivy JM, Kreiling JA. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging (Albany NY). 2013;5(12):867-83.
[62] Koch CM, Wagner W. Epigenetic biomarker to determine replicative senescence of cultured cells. Methods Mol Biol. 2013;1048:309-21.
[63] Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000;1(1):72-6.
[64] Rubin H. Telomerase and cellular lifespan: ending the debate? Nat Biotechnol. 1998;16(5):396-7.
[65] Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985;43(2 Pt 1):405-13.
[66] Morin GB. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989;59(3):521-9.
[67] Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266(5193):2011-5.
[68] Martens UM, Chavez EA, Poon SS, Schmoor C, Lansdorp PM. Accumulation of short telomeres in human fibroblasts prior to replicative senescence. Exp Cell Res. 2000;256(1):291-9.
[69] Baird DM, Rowson J, Wynford-Thomas D, Kipling D. Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat Genet. 2003;33(2):203-7.
[70] Martin-Ruiz C, Saretzki G, Petrie J, Ladhoff J, Jeyapalan J, Wei W, Sedivy J, von Zglinicki T. Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative life span. J Biol Chem. 2004;279(17):17826-33.
[71] Zou Y, Sfeir A, Gryaznov SM, Shay JW, Wright WE. Does a sentinel or a subset of short telomeres determine replicative senescence? Mol Biol Cell. 2004;15(8):3709-18.
[72] Chai W, Shay JW, Wright WE. Human telomeres maintain their overhang length at senescence. Mol Cell Biol. 2005;25(6):2158-68.
[73] Stewart SA, Ben-Porath I, Carey VJ, O'Connor BF, Hahn WC, Weinberg RA. Erosion of the telomeric single-strand overhang at replicative senescence. Nat Genet. 2003;33(4):492-6.
[74] Smogorzewska A, de Lange T. Different telomere damage signaling pathways in human and mouse cells. EMBO J. 2002;21(16):4338-48.
[75] Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T. Mammalian telomeres end in a large duplex loop. Cell. 1999;97(4):503-14.
[76] Celli GB, de Lange T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol. 2005;7(7):712-8.
[77] Hockemeyer D, Sfeir AJ, Shay JW, Wright WE, de Lange T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. EMBO J. 2005;24(14):2667-78.
[78] van Steensel B, de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature. 1997;385(6618):740-3.
[79] de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19(18):2100-10.
[80] d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP, Jackson SP. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194–8.
[81] Deng Y, Chan SS, Chang S. Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer. 2008;8(6):450-8.
[82] Peuscher MH, Jacobs JJ. DNA-damage response and repair activities at uncapped telomeres depend on RNF8. Nat Cell Biol. 2011;13(9):1139-45.
[83] Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov JM, Bucci G, Dobreva M, Matti V, Beausejour CM, Herbig U, Longhese MP, d’Adda di Fagagna F. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012;14(4):355–65.
[84] Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13(17):1549-56.
[85] Herbig U, Jobling WA, Chen BP, Chen DJ, Sedivy JM. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell. 2004;14(4):501-13.
[86] Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 1999;13(2):152-7.
[87] Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, Smorodinsky NI, Prives C, Reiss Y, Shiloh Y, Ziv Y. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science. 1998;281(5383):1674-7.
[88] Barlev NA, Liu L, Chehab NH, Mansfield K, Harris KG, Halazonetis TD, Berger SL. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Mol Cell. 2001;8(6):1243-54.
[89] Saramäki A, Banwell CM, Campbell MJ, Carlberg C. Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res. 2006;34(2):543-54.
[90] Alcorta DA, Xiong Y, Phelps D, Hannon G, Beach D, Barrett JC. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc Natl Acad Sci U S A. 1996;93(24):13742-7.
[91] Stein GH, Drullinger LF, Soulard A, Dulić V. Differential roles for cyclin-dependent kinase inhibitors p21 and p16 in the mechanisms of senescence and differentiation in human fibroblasts. Mol Cell Biol. 1999;19(3):2109-17.
[92] De Bont R, van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis. 2004;19(3):169-85.
[93] Ghosal G, Chen J. DNA damage tolerance: a double-edged sword guarding the genome. Transl Cancer Res. 2013;2(3):107-129. PMID: 24058901 PMCID: PMC3779140
[94] Suzuki K, Mori I, Nakayama Y, Miyakoda M, Kodama S, Watanabe M. Radiation-induced senescence-like growth arrest requires TP53 function but not telomere shortening. Radiat Res. 2001;155(1 Pt 2):248-253.
[95] Sabin RJ, Anderson RM. Cellular Senescence - its role in cancer and the response to ionizing radiation. Genome Integr. 2011;2(1):7.
[96] Chaturvedi V, Qin JZ, Stennett L, Choubey D, Nickoloff BJ. Resistance to UV-induced apoptosis in human keratinocytes during accelerated senescence is associated with functional inactivation of p53. J Cell Physiol. 2004;198(1):100-9.
[97] Lewis DA, Yi Q, Travers JB, Spandau DF. UVB-induced senescence in human keratinocytes requires a functional insulin-like growth factor-1 receptor and p53. Mol Biol Cell. 2008;19(4):1346-53.
[98] Wang Y, Blandino G, Oren M, Givol D. Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs. Oncogene. 1998;17(15):1923-30.
[99] Chen Q, Ames BN. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci U S A. 1994;91(10):4130-4.
[100] Macip S, Igarashi M, Fang L, Chen A, Pan ZQ, Lee SW, Aaronson SA. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 2002;21(9):2180-8.
[101] Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593-602.
[102] Ferbeyre G, de Stanchina E, Lin AW, Querido E, McCurrach ME, Hannon GJ, Lowe SW. Oncogenic ras and p53 cooperate to induce cellular senescence. Mol Cell Biol. 2002;22(10):3497-508.
[103] Lomax ME, Folkes LK, O'Neill P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin Oncol (R Coll Radiol). 2013;25(10):578-85.
[104] Dewey WC, Ling CC, Meyn RE. Radiation-induced apoptosis: relevance to radiotherapy. Int J Radiat Oncol Biol Phys. 1995;33(4):781-96.
[105] Di Leonardo A, Linke SP, Clarkin K, Wahl GM. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994;8(21):2540-51.
[106] Kim KS, Kim JE, Choi KJ, Bae S, Kim DH. Characterization of DNA damage-induced cellular senescence by ionizing radiation in endothelial cells. Int J Radiat Biol. 2014;90(1):71-80.
[107] Meng A, Wang Y, Van Zant G, Zhou D. Ionizing radiation and busulfan induce premature senescence in murine bone marrow hematopoietic cells. Cancer Res. 2003;63(17):5414-9.
[108] Wang Y, Schulte BA, LaRue AC, Ogawa M, Zhou D. Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood. 2006;107(1):358-66.
[109] Muthna D, Soukup T, Vavrova J, Mokry J, Cmielova J, Visek B, Jiroutova A, Havelek R, Suchanek J, Filip S, English D, Rezacova M. Irradiation of adult human dental pulp stem cells provokes activation of p53, cell cycle arrest, and senescence but not apoptosis. Stem Cells Dev. 2010;19(12):1855–62.
[110] Jones KR, Elmore LW, Jackson-Cook C, Demasters G, Povirk LF, Holt SE, Gewirtz DA. p53-Dependent accelerated senescence induced by ionizing radiation in breast tumour cells. Int J Radiat Biol. 2005;81(6):445-58.
[111] Kim BC, Han NK, Byun HO, Kim SS, Ahn EK, Chu IS, Leem SH, Lee CK, Lee JS. Time-dependently expressed markers and the characterization for premature senescence induced by ionizing radiation in MCF7. Oncol Rep. 2010;24(2):395-403.
[112] Luo H, Yount C, Lang H, Yang A, Riemer EC, Lyons K, Vanek KN, Silvestri GA, Schulte BA, Wang GY. Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence. Lung Cancer. 2013;81(2):167-73.
[113] Barreto-Andrade JC, Efimova EV, Mauceri HJ, Beckett MA, Sutton HG, Darga TE, Vokes EE, Posner MC, Kron SJ, Weichselbaum RR. Response of human prostate cancer cells and tumors to combining PARP inhibition with ionizing radiation. Mol Cancer Ther. 2011;10(7):1185-93.
[114] Kumar R, Horikoshi N, Singh M, Gupta A, Misra HS, Albuquerque K, Hunt CR, Pandita TK. Chromatin modifications and the DNA damage response to ionizing radiation. Front Oncol. 2013;2:214.
[115] Le ON, Rodier F, Fontaine F, Coppe JP, Campisi J, DeGregori J, Laverdière C, Kokta V, Haddad E, Beauséjour CM. Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell. 2010;9(3):398-409.
[116] Suzuki M, Suzuki K, Kodama S, Watanabe M. Interstitial chromatin alteration causes persistent p53 activation involved in the radiation-induced senescence-like growth arrest. Biochem Biophys Res Commun. 2006;340(1):145-50.
[117] Naka K, Tachibana A, Ikeda K, Motoyama N. Stress-induced premature senescence in hTERT-expressing ataxia telangiectasia fibroblasts. J Biol Chem. 2004;279(3):2030-7.
[118] Carbonneau CL, Despars G, Rojas-Sutterlin S, Fortin A, Le O, Hoang T, Beauséjour CM. Ionizing radiation-induced expression of INK4a/ARF in murine bone marrow-derived stromal cell populations interferes with bone marrow homeostasis. Blood. 2012;119(3):717-26.
[119] Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T. A senescent cell bystander effect: senescence-induced senescence. Aging Cell. 2012;11(2):345-9.
[120] Hong EH, Lee SJ, Kim JS, Lee KH, Um HD, Kim JH, Kim SJ, Kim JI, Hwang SG. Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase. J Biol Chem. 2010;285(2):1283-95.
[121] Dickey JS, Baird BJ, Redon CE, Sokolov MV, Sedelnikova OA, Bonner WM. Intercellular communication of cellular stress monitored by gamma-H2AX induction. Carcinogenesis. 2009;30(10):1686-95.
[122] Azzam EI, de Toledo SM, Little JB. Direct evidence for the participation of gap junction-mediated intercellular communication in the transmission of damage signals from alpha -particle irradiated to nonirradiated cells. Proc Natl Acad Sci U S A. 2001;98(2):473-8.
[123] Ravanat JL, Douki T, Cadet J. Direct and indirect effects of UV radiation on DNA and its components. J Photochem Photobiol B. 2001;63(1-3):88-102.
[124] Sinha RP, Häder DP. UV-induced DNA damage and repair: a review. Photochem Photobiol Sci. 2002;1(4):225-36.
[125] Sugasawa K, Okuda Y, Saijo M, Nishi R, Matsuda N, Chu G, Mori T, Iwai S, Tanaka K, Tanaka K, Hanaoka F. UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex. Cell. 2005;121(3):387-400.
[126] Scott AD, Waters R. Inducible nucleotide excision repair (NER) of UV-induced cyclobutane pyrimidine dimers in the cell cycle of the budding yeast Saccharomyces cerevisiae: evidence that inducible NER is confined to the G1 phase of the mitotic cell cycle. Mol Gen Genet. 1997;254(1):43-53.
[127] Slieman TA, Nicholson WL. Artificial and solar UV radiation induces strand breaks and cyclobutane pyrimidine dimers in Bacillus subtilis spore DNA. Appl Environ Microbiol. 2000;66(1):199-205.
[128] Baumstark-Khan C, Hentschel U, Nikandrova Y, Krug J, Horneck G. Fluorometric analysis of DNA unwinding (FADU) as a method for detecting repair-induced DNA strand breaks in UV-irradiated mammalian cells. Photochem Photobiol. 2000;72(4):477-84.
[129] Batista LF, Kaina B, Meneghini R, Menck CF. How DNA lesions are turned into powerful killing structures: insights from UV-induced apoptosis. Mutat Res. 2009;681(2-3):197-208.
[130] Limoli CL, Giedzinski E, Bonner WM, Cleaver JE. UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, gamma -H2AX formation, and Mre11 relocalization. Proc Natl Acad Sci U S A. 2002;99(1):233-8.
[131] Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003;100(22):12871-6.
[132] Greinert R, Volkmer B, Henning S, Breitbart EW, Greulich KO, Cardoso MC, Rapp A. UVA-induced DNA double-strand breaks result from the repair of clustered oxidative DNA damages. Nucleic Acids Res. 2012;40(20):10263-73.
[133] Staszewski O, Nikolova T, Kaina B. Kinetics of gamma-H2AX focus formation upon treatment of cells with UV light and alkylating agents. Environ Mol Mutagen. 2008;49(9):734-40.
[134] Wu X, Shell SM, Liu Y, Zou Y. ATR-dependent checkpoint modulates XPA nuclear import in response to UV irradiation. Oncogene. 2007;26(5):757-64.
[135] Kamarajan P, Chao CC. UV-induced apoptosis in resistant HeLa cells. Biosci Rep. 2000;20(2):99-108.
[136] Assefa Z, Van Laethem A, Garmyn M, Agostinis P. Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors. Biochim Biophys Acta. 2005;1755(2):90-106.
[137] Chainiaux F, Magalhaes JP, Eliaers F, Remacle J, Toussaint O. UVB-induced premature senescence of human diploid skin fibroblasts. Int J Biochem Cell Biol. 2002;34(11):1331-9.
[138] Borlon C, Chretien A, Debacq-Chainiaux F, Toussaint O. Transient increased extracellular release of H2O2 during establishment of UVB-induced premature senescence. Ann N Y Acad Sci. 2007;1119:72-7.
[139] Jee HJ, Kim HJ, Kim AJ, Bae YS, Bae SS, Yun J. UV light induces premature senescence in Akt1-null mouse embryonic fibroblasts by increasing intracellular levels of ROS. Biochem Biophys Res Commun. 2009;383(3):358-62.
[140] Latonen L, Taya Y, Laiho M. UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts. Oncogene. 2001;20(46):6784-93.
[141] Bertrand-Vallery V, Boilan E, Ninane N, Demazy C, Friguet B, Toussaint O, Poumay Y, Debacq-Chainiaux F. Repeated exposures to UVB induce differentiation rather than senescence of human keratinocytes lacking p16(INK-4A). Biogerontology. 2010;11(2):167-81.
[142] Chazal M, Marionnet C, Michel L, Mollier K, Dazard JE, Della Valle V, Larsen CJ, Gras MP, Basset-Séguin N. P16(INK4A) is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation. Oncogene. 2002;21(17):2652-61.
[143] Pavey S, Conroy S, Russell T, Gabrielli B. Ultraviolet radiation induces p16CDKN2A expression in human skin. Cancer Res. 1999;59(17):4185-9.
[144] Al-Mohanna MA, Manogaran PS, Al-Mukhalafi Z, A Al-Hussein K, Aboussekhra A. The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. Oncogene. 2004;23(1):201–12.
[145] Lu T, Finkel T. Free radicals and senescence. Exp Cell Res. 2008;314(9):1918-22.
[146] Furumoto K, Inoue E, Nagao N, Hiyama E, Miwa N. Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress. Life Sci. 1998;63(11):935-48.
[147] Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A. 1995;92(10):4337-41.
[148] Saretzki G, Murphy MP, von Zglinicki T. MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress. Aging Cell. 2003;2(2):141-3.
[149] Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER. Age-related changes in oxidized proteins. J Biol Chem. 1987;262(12):5488-91.
[150] Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN. Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A. 1990;87(12):4533-7.
[151] Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, Fraifeld VE. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev. 2013;12(2):661-84.
[152] Allen RG, Tresini M, Keogh BP, Doggett DL, Cristofalo VJ. Differences in electron transport potential, antioxidant defenses, and oxidant generation in young and senescent fetal lung fibroblasts (WI-38). J Cell Physiol. 1999;180(1):114-22.
[153] Lener B, Kozieł R, Pircher H, Hütter E, Greussing R, Herndler-Brandstetter D, Hermann M, Unterluggauer H, Jansen-Dürr P. The NADPH oxidase Nox4 restricts the replicative lifespan of human endothelial cells. Biochem J. 2009;423(3):363-74.
[154] Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A. 5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation. EMBO J. 2005;24(1):170-9.
[155] Chen QM, Bartholomew JC, Campisi J, Acosta M, Reagan JD, Ames BN. Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J. 1998;332 ( Pt 1):43–50.
[156] Duan J, Duan J, Zhang Z, Tong T. Irreversible cellular senescence induced by prolonged exposure to H2O2 involves DNA-damage-and-repair genes and telomere shortening. Int J Biochem Cell Biol. 2005;37(7):1407-20.
[157] Zdanov S, Remacle J, Toussaint O. Establishment of H2O2-induced premature senescence in human fibroblasts concomitant with increased cellular production of H2O2. Ann N Y Acad Sci. 2006;1067:210-6.
[158] Dumont P, Burton M, Chen QM, Gonos ES, Frippiat C, Mazarati JB, Eliaers F, Remacle J, Toussaint O. Induction of replicative senescence biomarkers by sublethal oxidative stresses in normal human fibroblast. Free Radic Biol Med. 2000;28(3):361-73.
[159] Chen X, Zhang J, Fang Y, Zhao C, Zhu Y. Ginsenoside Rg1 delays tert-butyl hydroperoxide-induced premature senescence in human WI-38 diploid fibroblast cells. J Gerontol A Biol Sci Med Sci. 2008;63(3):253-64.
[160] Moiseeva O, Mallette FA, Mukhopadhyay UK, Moores A, Ferbeyre G. DNA damage signaling and p53-dependent senescence after prolonged beta-interferon stimulation. Mol Biol Cell. 2006;17(4):1583-92.
[161] Jeong SG, Cho GW. Endogenous ROS levels are increased in replicative senescence in human bone marrow mesenchymal stromal cells. Biochem Biophys Res Commun. 2015;460(4):971-6.
[162] Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, Yu ZX, Ferrans VJ, Howard BH, Finkel T. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem. 1999;274(12):7936-40.
[163] Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010;6:347.
[164] Rai P, Onder TT, Young JJ, McFaline JL, Pang B, Dedon PC, Weinberg RA. Continuous elimination of oxidized nucleotides is necessary to prevent rapid onset of cellular senescence. Proc Natl Acad Sci U S A. 2009;106(1):169-74.
[165] von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 2002;27(7):339-44.
[166] Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. J Biol Chem. 1997;272(33):20313-6.
[167] Meyer M, Schreck R, Baeuerle PA. H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J. 1993;12(5):2005-15.
[168] Gupta A, Rosenberger SF, Bowden GT. Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed mouse keratinocyte cell lines. Carcinogenesis. 1999;20(11):2063-73.
[169] Patten DA, Lafleur VN, Robitaille GA, Chan DA, Giaccia AJ, Richard DE. Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species. Mol Biol Cell. 2010;21(18):3247-57.
[170] Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446-51.
[171] Kim J, Wong PK. Oxidative stress is linked to ERK1/2-p16 signaling-mediated growth defect in ATM-deficient astrocytes. J Biol Chem. 2009;284(21):14396-404.
[172] Russo T, Zambrano N, Esposito F, Ammendola R, Cimino F, Fiscella M, Jackman J, O'Connor PM, Anderson CW, Appella E. A p53-independent pathway for activation of WAF1. CIP1 expression following oxidative stress. J Biol Chem. 1995;270(49):29386–91.
[173] Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol. 2006;8(11):1291-7.
[174] Minamino T, Mitsialis SA, Kourembanas S. Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol. 2001;21(10):3336-42.
[175] Sullivan R, Paré GC, Frederiksen LJ, Semenza GL, Graham CH. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther. 2008;7(7):1961-73.
[176] Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle. 2009;8(12):1888-95.
[177] Leontieva OV, Natarajan V, Demidenko ZN, Burdelya LG, Gudkov AV, Blagosklonny MV. Hypoxia suppresses conversion from proliferative arrest to cellular senescence. Proc Natl Acad Sci U S A. 2012;109(33):13314-8.
[178] Klimova TA, Bell EL, Shroff EH, Weinberg FD, Snyder CM, Dimri GP, Schumacker PT, Budinger GR, Chandel NS. Hyperoxia-induced premature senescence requires p53 and pRb, but not mitochondrial matrix ROS. FASEB J. 2009;23(3): 783–94.
[179] Watson JA, Watson CJ, McCrohan AM, Woodfine K, Tosetto M, McDaid J, Gallagher E, Betts D, Baugh J, O'Sullivan J, Murrell A, Watson RW, McCann A. Generation of an epigenetic signature by chronic hypoxia in prostate cells. Hum Mol Genet. 2009;18(19):3594–604.
[180] Wang W, Wang D, Li H. Initiation of premature senescence by Bcl-2 in hypoxic condition. Int J Clin Exp Pathol. 2014;7(5):2446-53.
[181] Mo J, Sun B, Zhao X, Gu Q, Dong X, Liu Z, Ma Y, Zhao N, Tang R, Liu Y, Chi J, Sun R. Hypoxia-induced senescence contributes to the regulation of microenvironment in melanomas. Pathol Res Pract. 2013;209(10):640-7.
[182] Welford SM, Giaccia AJ. Hypoxia and senescence: the impact of oxygenation on tumor suppression. Mol Cancer Res. 2011;9(5):538-44.
[183] Blagosklonny MV. Geroconversion: irreversible step to cellular senescence. Cell Cycle. 2014;13(23):3628-35.
[184] Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010;10(1):51-7.
[185] Larsson LG. Oncogene- and tumor suppressor gene-mediated suppression of cellular senescence. Semin Cancer Biol. 2011;21(6):367-76.
[186] Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436(7051):725–30.
[187] Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, Hollstein PE, MacCollin M, Cichowski K. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006;10(6):459-72.
[188] Young AP, Schlisio S, Minamishima YA, Zhang Q, Li L, Grisanzio C, Signoretti S, Kaelin WG Jr. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol. 2008;10(3):361-9.
[189] Hemann MT, Narita M. Oncogenes and senescence: breaking down in the fast lane. Genes Dev. 2007;21(1):1-5.
[190] Toledo LI, Murga M, Gutierrez-Martinez P, Soria R, Fernandez-Capetillo O. ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev. 2008;22(3):297-302.
[191] Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C, Schurra C, Garre’ M, Nuciforo PG, Bensimon A, Maestro R, Pelicci PG, d’Adda di Fagagna F. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444(7119):638–42.
[192] Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Ørntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633-7.
[193] Mallette FA, Gaumont-Leclerc MF, Ferbeyre G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev. 2007;21(1):43-8.
[194] Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, Wahl GM. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell. 2002;9(5):1031-44.
[195] Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science. 1997;275(5306):1649-52.
[196] Dolado I, Swat A, Ajenjo N, De Vita G, Cuadrado A, Nebreda AR. p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell. 2007;11(2):191-205.
[197] Ogrunc M, Di Micco R, Liontos M, Bombardelli L, Mione M, Fumagalli M, Gorgoulis VG, d'Adda di Fagagna F. Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation. Cell Death Differ. 2014;21(6):998–1012.
[198] Maya-Mendoza A, Ostrakova J, Kosar M, Hall A, Duskova P, Mistrik M, Merchut-Maya JM, Hodny Z, Bartkova J, Christensen C, Bartek J. Myc and Ras oncogenes engage different energy metabolism programs and evoke distinct patterns of oxidative and DNA replication stress. Mol Oncol. 2015;9(3):601-16.
[199] Suram A, Kaplunov J, Patel PL, Ruan H, Cerutti A, Boccardi V, Fumagalli M, Di Micco R, Mirani N, Gurung RL, Hande MP, d’Adda di Fagagna F, Herbig U. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 2012;31(13):2839–51.
[200] Neelsen KJ, Zanini IM, Herrador R, Lopes M. Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. J Cell Biol. 2013;200(6):699-708.
[201] Aird KM, Zhang G, Li H, Tu Z, Bitler BG, Garipov A, Wu H, Wei Z, Wagner SN, Herlyn M, Zhang R. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Rep. 2013;3(4):1252-65.
[202] Ribeiro JD, Morey L, Mas A, Gutierrez A, Luis NM, Mejetta S, Richly H, Benitah SA, Keyes WM, Di Croce L. ZRF1 controls oncogene-induced senescence through the INK4-ARF locus. Oncogene. 2013;32(17):2161-8.
[203] Sreeramaneni R, Chaudhry A, McMahon M, Sherr CJ, Inoue K. Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor. Mol Cell Biol. 2005;25(1):220-32.
[204] Vogt M, Haggblom C, Yeargin J, Christiansen-Weber T, Haas M. Independent induction of senescence by p16INK4a and p21CIP1 in spontaneously immortalized human fibroblasts. Cell Growth Differ. 1998;9(2):139-46.
[205] Zhu J, Woods D, McMahon M, Bishop JM. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 1998;12(19):2997-3007.
[206] Uhrbom L, Nistér M, Westermark B. Induction of senescence in human malignant glioma cells by p16INK4A. Oncogene. 1997;15(5):505-14.
[207] Efeyan A, Murga M, Martinez-Pastor B, Ortega-Molina A, Soria R, Collado M, Fernandez-Capetillo O, Serrano M. Limited role of murine ATM in oncogene-induced senescence and p53-dependent tumor suppression. PLoS One. 2009;4(5):e5475.
[208] Astle MV, Hannan KM, Ng PY, Lee RS, George AJ, Hsu AK, Haupt Y, Hannan RD, Pearson RB. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene. 2012;31(15):1949-62.
[209] Sharpless NE, Ramsey MR, Balasubramanian P, Castrillon DH, DePinho RA. The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis. Oncogene. 2004;23(2):379-85.
[210] Tao W, Levine AJ. P19(ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci U S A. 1999;96(12):6937-41.
[211] Weber JD, Jeffers JR, Rehg JE, Randle DH, Lozano G, Roussel MF, Sherr CJ, Zambetti GP. p53-independent functions of the p19(ARF) tumor suppressor. Genes Dev. 2000;14(18):2358-65.
[212] Haferkamp S, Scurr LL, Becker TM, Frausto M, Kefford RF, Rizos H. Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors. J Invest Dermatol. 2009;129(8):1983-91.
[213] Ohtani N, Zebedee Z, Huot TJ, Stinson JA, Sugimoto M, Ohashi Y, Sharrocks AD, Peters G, Hara E. Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature. 2001;409(6823):1067-70.
[214] Lin AW, Barradas M, Stone JC, van Aelst L, Serrano M, Lowe SW. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12(19):3008-19.
[215] Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, Majoor DM, Shay JW, Mooi WJ, Peeper DS. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720-4.
[216] Dhomen N, Reis-Filho JS, da Rocha Dias S, Hayward R, Savage K, Delmas V, Larue L, Pritchard C, Marais R. Oncogenic Braf induces melanocyte senescence and melanoma in mice. Cancer Cell. 2009;15(4):294-303.
[217] Vredeveld LC, Possik PA, Smit MA, Meissl K, Michaloglou C, Horlings HM, Ajouaou A, Kortman PC, Dankort D, McMahon M, Mooi WJ, Peeper DS. Abrogation of BRAFV600E-induced senescence by PI3K pathway activation contributes to melanomagenesis. Genes Dev. 2012;26(10):1055-69.
[218] Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, Benguría A, Zaballos A, Flores JM, Barbacid M, Beach D, Serrano M. Tumour biology: senescence in premalignant tumours. Nature. 2005;436(7051):642.