Cellular senescence and tumor suppressor gene p16

International Journal of Cancer

Volumn 130, Issue 8, 2012, Pages 1715-1725

  Rayess, Hani ^a,b   Wang, Marilene B ^a   Srivatsan, Eri S ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

senescence; tumor suppressor gene p16

Indexed keywords

BMI1 PROTEIN; CELL PROTEIN; CYCLIN DEPENDENT KINASE; DNA; HISTONE DEACETYLASE; INHIBITOR OF DIFFERENTIATION 1; POMBE REPRESSOR COMPLEX 1; POMBE REPRESSOR COMPLEX 2; PROTEIN P16; PROTEIN P53; RETINOBLASTOMA PROTEIN; TRANSCRIPTION FACTOR CTCF; TRANSCRIPTION FACTOR E2F1; TRANSCRIPTION FACTOR ETS; TRANSCRIPTION FACTOR SP1; TRANSCRIPTION FACTOR YY1; UNCLASSIFIED DRUG;

AGING; ARTICLE; CANCER PREVENTION; CELL AGING; CELL CYCLE REGULATION; CELL STRUCTURE; CYTOPLASM; DISORDERS OF MITOCHONDRIAL FUNCTIONS; DNA DAMAGE; ENDOPLASMIC RETICULUM; ENZYME INHIBITION; EPIGENETICS; G1 PHASE CELL CYCLE CHECKPOINT; GENE ACTIVATION; GENE EXPRESSION REGULATION; HUMAN; INTRACELLULAR SIGNALING; LYSOSOME; NONHUMAN; ONCOGENE; OXIDATIVE STRESS; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; TELOMERE SHORTENING; TRANSCRIPTION INITIATION; TUMOR SUPPRESSOR GENE;

ANTINEOPLASTIC AGENTS; CELL AGING; CELL CYCLE CHECKPOINTS; CYCLIN-DEPENDENT KINASE INHIBITOR P16; GENE EXPRESSION; HUMANS; NEOPLASMS; RETINOBLASTOMA PROTEIN; TELOMERE SHORTENING; TUMOR SUPPRESSOR PROTEIN P53;

EID: 84857504660     PISSN: 00207136     EISSN: 10970215     Source Type: Journal    
DOI: 10.1002/ijc.27316     Document Type: Article

References (125)

1. Nuss JE, Choksi KB, DeFord JH, Papaconstantinou J,. Decreased enzyme activities of chaperones PDI and BiP in aged mouse livers. Biochem Biophys Res Commun 2008; 365: 355-61.
2. Kaufman RJ,. Orchestrating the unfolded protein response in health and disease. J Clinical Invest 2002; 110: 1389-98.
3. Rabek JP, Boylston H III., Carbonylation of ER chaperone proteins in aged mouse liver. Biochem Biophys Res Commun 2003; 305: 566-72.
4. Kornfeld R, Kornfeld S,. Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem 1985; 54: 631-64.
5. Erickson RR, Dunning LM, Holtzman JL,. The effect of aging on the chaperone concentrations in the hepatic, endoplasmic reticulum of male rats: the possible role of protein misfolding due to the loss of chaperones in the decline in physiological function seen with age. J Gerontol A Biol Sci Med Sci 2006; 61: 435-43.
6. Yin D, Kuczera K, Squier TC,. The sensitivity of carboxyl-terminal methionines in calmodulin isoforms to oxidation by H2O2 modulates the ability to activate the plasma membrane Ca-ATPase. Chem Res Toxicol 2000; 13: 103-10.
7. De Grey AD,. A proposed refinement of the mitochondrial free radical theory of aging. Bioessays 1997; 19: 161-66.
8. Harman D,. The biologic clock: the mitochondria? J Am Geriatric Soc 1972; 20: 145-47.
9. Terman A, Gustafsson B, Brunk UT,. Mitochondrial damage and intralysosomal degradation in cellular aging. Mol Aspects Med 2007; 27: 471-82.
10. Khrapko K, Bodyak N, Thilly WG, van Orsouw NJ, Zhang X, Coller HA, Perls TT, Upton M, Vijg J, Wei JY,. Cell by- cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions. Nucleic Acids Res 1999; 27: 2434-41.
11. Cao Z WJ, McKiernan SH, Aiken JM,. Mitochondrial DNA deletion mutations are concomitant with ragged red regions of individual, aged muscle fibers: analysis by laser capture microdissection. Nucleic Acids Res 2001; 29: 4502-8.
12. Miwa SLC, von Zglinicki T,. Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model. Aging Cell 2008; 7: 920-23.
13. Brunk UT, Terman A,. Lipofuscin: mechanisms of agerelated accumulation and influence on cell functions. Free Radic Biol Med 2002; 33: 611-19.
14. Brunk UT, Terman A,. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 2002; 269: 1996-02.
15. Spiteller G,. Linoleic acid peroxidationâ€"the dominant lipid peroxidation process in low density lipoproteinâ€"and its relationship to chronic diseases. Chem Phys Lipids 1998; 95: 105-62.
16. Dudda A, Spiteller G, Kobalt F,. Lipid oxidation products in ischemic porcine heart tissue. Chem Phys Lipids 1996; 82: 39-51.
17. Lazzerini Denchi E, Attwooll C, Pasini D, Helin K,. Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland. Mol Cell Biol 2005; 25: 2660-72.
18. Rowland BD, Bernards R,. Re-evaluating cell-cycle regulation by E2Fs. Cell 2006; 127: 871-74.
19. Li CM, Villasante A, Strati K, Ortega S, Cañamero M, Blasco MA, Serrano M,. The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 2009; 460: 1136-39.
20. Li Y, Nichols MA, Shay JW, Xiong Y,. Transcriptional repression of the D-type cyclin-dependent kinase inhibitor p16 by the retinoblastoma susceptibility gene product pRb. Cancer Res 1994; 54: 6078-72.
21. Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G,. Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence. Mol Cell Biol 1996; 16: 859-67.
22. 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: 5414-19.
23. Wang Y, Schulte BA, Larue AC, Ogawa M, Zhou D,. Total body irradiation selectively induces murine hematopoietic stem cell senescence. Blood 2006; 107: 359-66.
24. 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: 1291-97.
25. Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE,. Ink4a/Arf expression is a biomarker of aging. J Clin Invest 2004; 114: 1299-07.
26. Reynisdottir I, Polyak K, Iavarone A, Massague J,. Kip/Cip and Ink4 Cdk inhibitors cooperate to induce cell cycle arrest in response to TGF-beta. Genes Dev 1995; 9: 1831-45.
27. Kim WY, Sharpless N E,. The regulation of INK4/ ARF in cancer and aging. Cell 2006; 127: 265-75.
28. Quelle DE, Zindy F, Ashmun RA, Sherr CJ,. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cyle arrest. Cell 1995; 8: 993-1000.
29. Sparmann A, Van Louhizen LM,. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer 2006; 6: 846-56.
30. Schwartz YB, Pirrotta V,. Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Gene 2007; 8: 9-22.
31. Hernandez-Munoz I, Taghavi P, Kuijl C, Neefjes J, Van Lohuizen M,. Association of BMI1 with polycomb bodies is dynamic and requires PRC2/ EZH2 and the maintenance DNA methyltransferase DNMT1. Mol Cell Biol 2005; 25: 11047-58.
32. Saurin AJ, Shao Z, Erdjument-Bromage H, Tempst P, Kingston RE,. A Drosophila Polycomb group complex includes Zeste and dTAFII proteins. Nature 2001; 412: 655-60.
33. Shao Z, Raible F, Mollaaghababa R, Guyon JR, Wu CT, Bender W, Kingston RE,. Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell Biology 1999; 98: 37-46.
34. Gil J, Bernard D, Martinez D, Beach D,. Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 2006; 7: 667-77.
35. Whitcomb SJ, Basu A, Allis CD, Bernstein E,. Polycomb Group proteins: an evolutionary perspective. Trends Genet 2007; 23: 494-2.
36. Maertens G, Messaoudi-Aubert S,. Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor. The EMBO J 2010; 29: 2553-65.
37. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones R, Zhang Y,. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 2002; 298: 1039-43.
38. Czermin B, Melfi R, McCabe D, Seitz V, Imhof A, Pirrotta V,. Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyl-transferase activity that marks chromosomal Polycomb sites. Cell Biol 2002; 111: 185-96.
39. Müller J, Hart CM, Francis NJ, Vargas ML, Sengupta A, Wild B, Miller EL, O'Connor MB, Kingston RE, Simon JA,. Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell Biol 2002; 111: 197-208.
40. Cao RZY,. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opinion Gene Dev 2004; 14: 155-64.
41. Kuzmichev A, Tempst P, Reinberg D,. Different EZH2-containing complexes target methylation of histone H1 or nucleosomal histone H3. Mol Cell 2004; 14: 183-93.
42. Bracken AP, Dietrich N, Pasini D, Gargiulo G,. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 2007; 21: 525-30.
43. Bannister AJ, Zegerman P,. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 2001; 410: 120-24.
44. Ball LJ, Murzina NV, Broadhurst RW, Raine AR, Archer SJ, Stott FJ, Murzin AG, Singh PB, Domaille PJ, Laue ED,. Structure of the chromatin binding (chromo) domain from mouse modifier protein 1. EMBO J 1997; 16: 273-81.
45. Sherr CJ, Roberts JM,. Living with or without cyclins and cyclin-dependent kinases. Genes Dev 2004; 18: 2699-2711.
46. Negishi M, Saraya A, Mochizuki S, Helin K, Koseki H, Iwama A,. A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/Arf locus through polycomb repressive complex 1. PLos One 2010; 5: e12373.
47. Bruggeman SW, Valk-Lingbeek ME, van der Stoop PP, Jacobs JJ, Kieboom K, Tanger E, Hulsman D, Leung C, Arsenijevic Y, Marino S, Van Lohuizen M,. Ink4a and Arf differentially affect cell proliferation and neural stem cell self-renewal in Bmi1-deficient mice. Genes Dev 2005; 19: 1438-43.
48. Molofsky AV, He S, Bydon M, Morrison SJ, Pardal R,. Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 2005; 19: 1432-37.
49. Kotake YRC, Viatour P, Sage J, Zhang Y, Xiong Y,. pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene. Genes Dev 2006; 21: 49-54.
50. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH,. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. EMBO J 2007; 26: 1637-48.
51. Bernard D, Martinez-Leal JF, Rizzo S, Martinez D, Hudson D, Visakorpi T, Peters G, Carnero A, Beach D, Gil J,. CBX7 controls the growth of normal and tumor-derived prostate cells by repressing the Ink4a/Arf locus. Oncogene 2005; 24: 5543-51.
52. Maertens GN, El Messaoudi-Aubert S, Racek T, Stock JK, Nicholls J, Rodriguez-Niedenführ M, Gil J, Peters G,. Several distinct polycomb complexes regulate and co-localize on the INK4a tumor suppressor locus. PloS One 2009; 4: e6380.
53. Yap KL, Li S, Muñoz-Cabello AM, Raguz S, Zeng L, Mujtaba S, Gil J, Walsh MJ, Zhou MM,. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 Lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Mol Cell 2010; 38: 662-74.
54. Lachner M, O'Caroll D, Rea S, Mechtler K, Jenuwein T,. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 2001; 410: 116-20.
55. Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T,. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 2001; 410: 120-24.
56. Dou Y, Milne TA, Ruthenburg AJ, Lee S, Lee JW, Verdine GL, Allis CD, Roeder RG,. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 2006; 13: 713-19.
57. Terranova R, Agherbi H, Boned A, Meresse S, Djabali M,. Histone and DNA methylation defects at Hox genes in mice expressing a SET domaintruncated form of Mll. Proc Natl Acad Sci USA 2006; 103: 6629-34.
58. Dietrich N, Bracken AP, Trinh E, Schjerling CK, Koseki H, Rappsilber J, Helin K, Hansen KH,. Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus. Embo J 2007; 26: 1637-48.
59. Gil J, Bernard D, Martínez D, Beach D,. Polycomb CBX7 has a unifying role in cellular lifespan. Nat Cell Biol 2004; 6: 67-72.
60. Nekrasov M, Klymenko T, Fraterman S, Papp B, Oktaba K, Köcher T, Cohen A, Stunnenberg HG, Wilm M, Müller J,. Pcl-PRC2 isneeded to generate high levels of H3-K27 trimethylation at Polycomb target genes. EMBO J 2007; 26: 4078-88.
61. Li X, Isono K, Yamada D, Endo TA, Endoh M, Shinga J, Mizutani-Koseki Y, Otte AP, Casanova M, Kitamura H, Kamijo T, Sharif J, et al. Mammalian polycomb-like Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate polycomb activity both at the Hox gene cluster and at Cdkn2a genes. Mol Cell 2011; 31: 351-64.
62. Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D,. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 2002; 16: 2893-3005.
63. Van der Vlag J, Otte AP,. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet 1999; 23: 474-78.
64. Bhalla KN,. Epigenetic and chromatin modifiers as targeted therapy of hematologic malignancies. Clin Oncol 2005; 23: 3971-93.
65. Yamaguchi J, Sasaki M, Sato Y, Itatsu K, Harada K, Zen Y, Ikeda H, Nimura Y, Nagino M, Nakanuma Y,. Histone deacetylase inhibitor (SAHA) and repression of EZH2 synergistically inhibit proliferation of gallbladder carcinoma. Japanese Cancer Asso 2009; 10: 355-62.
66. Ringrose L, Paro R,. Polycomb/trithorax response elements and epigenetic memory of cell identity. Development 2007; 134: 223-32.
67. Schuettengruber B, Chourrout B, Vervoort M, Leblanc B, Cavalli G,. Genome regulation by Polycomb and Trithorax proteins. Cell Biol 2007; 128: 735-45.
68. Klochendler-Yeivin A, Muchardt M, Yaniv M,. SWI/SNF chromatin remodeling and cancer. Curr Opin Gene Dev 2002; 12: 73-79.
69. Sevenet N, Sheridan E, Amram D, Schneider D, Handgretinger R, Delattre O,. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 1999; 65: 1342-48.
70. Kia SK, Gorski MM, Giannakopoulos S, Verrijzer CP,. SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol Cell Biol 2008; 28: 3457-64.
71. Jung JW, Lee S, Seo MS, Park SB, Kurtz A, Kang KS,. Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3. Cell Mol Life Sci 2010; 7: 1165-76.
72. Feng Y, Wang X, Xu L, Pan H, Zhu S, Liang Q, Huang B, Lu J,. The transcription factor ZBP-89 suppresses p16 expression through a histone modification mechanism to affect cell senescence. FEBS J 2009; 15: 4197-4206.
73. Wang X, Feng Y, Xu L, Chen Y, Zhang Y, Su D, Ren G, Lu J, Huang B,. YY1 restrained cell senescence through repressing the transcription of p16. Biochim Biophys Acta 2008; 1783: 1876-73.
74. Gonzalez S, Serrano M,. A new mechanism of inactivation of the INK4/ ARF locus. Cell Cycle 2006; 5: 1382-84.
75. Song J, Sandoval R, Pilkinton MA, Tian X, Raychaudhuri P, Colamonici OR,. ARF-induced downregulation of Mip130/LIN-9 protein levels mediates a positive feedback that leads to increased expression of p16Ink4a and p19Arf. Oncogene 2010; 29: 1976-86.
76. Sugimoto K, Kage H, Aki N, Sano A, Kitagawa H, Nagase T, Yatomi Y, Ohishi N, Takai D,. The induction of H3K9 methylation by PIWIL4 at the p16Ink4a locus. Biochem Biophys Res Commun 2007; 359: 497-502.
77. Tahbaz N, Kolb FA, Zhang H, Jaronczyk K, Filipowicz W, Hobman TC,. Characterization of the interactions between mammalian PAZ PIWI domain proteins and Dicer. EMBO Reports 2004; 5: 189-94.
78. Angel P, Karin M,. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991; 1079: 129-57.
79. Gil J, Peters G,. Regulation of the INK4b-ARFINK4a tumor suppressor locus: All for one or one for all. Nat Rev 2006; 7: 667-77.
80. Huang YC, Saito S, Yokoyama KK,. Histone chaperone Jun dimerization protein 2 (JDP2): role in cellular senescence and aging. Kaohsiung J Med Sci 2010; 26: 515-31.
81. Ostrovsky O, Bengal E, Aronheim A,. Induction of terminal differentiation by the c-Jun dimerization protein JDP2 in C2 myoblasts and rhabdomyosarcoma cells. J Biol Chem 2002; 277: 40043-54.
82. Nakade K, Pan J, Yamasaki T, Murata T, Wasylyk B, Yokoyama KK,. JDP2 (Jun Dimerization Protein 2)-deficient mouse embryonic fibroblasts are resistant to replicative senescence. J Biol Chem 2009; 284: 24415-24.
83. Choi BY, Choi HS, Ko K, Cho Y-Y, Zhu F, Kang BS, Ermakova SP, Ma W-Y, Bode A M, Dong Z,. The tumor suppressor p16INK4a prevents cell transformation through inhibition of c-Jun phosphorylation and AP-1 activity. Nat Struct Mol Biol 2005; 12: 699-707.
84. Witcher M, Emerson BM,. Epigenetic silencing of the p16INK4a tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. Mol Cell 2009; 34: 271-84.
85. Raisner RM, Madhani HD,. Patterning chromatin: form and function for H2A.Z variant nucleosomes. Curr Opin Genet Dev 2006; 16: 119-24.
86. Filippova GN,. Genetics and epigenetics of the multifunctional protein CTCF. Curr Top Dev Biol 2008; 80: 337-60
87. Wallace JA, Felsenfeld G,. We gather together: insulators and genome organization. Curr Opin Genet Dev 2007; 17: 400-7.
88. Chan HM, La Thangue NB,. p300/CBP proteins: HATs for transcriptional bridges and scaffold. J Cell Sci 2001; 114: 2363-73.
89. Wang X, Pan L, Feng Y, Wang Y, Han Q, Han L, Han S, Guo J, Huang B, Lu J,. p300 plays a role in p16INK4a expression and cell cycle arrest. Oncogene 2008; 27: 1894-1904.
90. Gan Q, Huang J, Zhou R, Niu J, Zhu X, Wang J., Zhang Z, Tong T,. PPAR accelerates cellular senescence by inducing p16INK4 expression in human diploid fibroblasts. J Cell Sci 2008; 131: 2235-45.
91. 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: 3008-3019.
92. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, et al. Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 2005; 8: 19-31.
93. Foos G, García-Ramírez JJ, Galang CK, Hauser CA,. Elevated expression of Ets2 or distinct portions of Ets 2 can reverse ras mediated celullar transformation. J Biol Chem 1998: 273: 18871-80.
94. 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: 1067-70.
95. Xiu M, Kim J, Sampson E, Huang CY, Davis RJ, Paulson, KE, Yee AS,. The transcriptional repressor HBP1 is a target of the p38 mitogen-activated protein kinase pathway in cell cycle regulation. Mol Cell 2003; 23: 8890-901.
96. Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez- Niedenführ M, Maertens G, Banck M, Zhou MM, Walsh MJ, Peters G, Gil J,. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev 2009; 23: 1177-82.
97. Yamakoshi K, Takahashi A, Hirota F, Nakayama R, Ishimaru N, Kubo Y, Mann DJ, Ohmura M, Hirao A, Saya H, Arase S, Hayashi Y, et al. Real-time in vivo imaging of p16Ink4a reveals cross talk with p53. J Cell Biol 2009; 186: 393-407.
98. Vousden KH, Lane DP,. p53 in health and disease. Nat Rev Cell Biol 2007; 8: 275-83.
99. Zhang D, Shimizu T, Araki N, Hirota T, Yoshie M, Ogawa K, Nakagata N, Takeya M, Saya H,. Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice. Oncogene 2008; 27: 4305-14.
100. Jung MS, Jin DH, Chae HD, Kang S, Kim SC, Bang YJ, Choi TS, Choi KS, Shin DY,. Bcl-xL and E1B-19K proteins inhibit p53- induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation. J Biol Chem 2004; 279: 17765-71.
101. Iwasa H, Han J, Ishikawa F,. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 2003; 8: 131-34.
102. Fujikawa M, Katagiri T, Tugores A, Nakamura Y, Ishikawa F,. ESE-3, an Ets family transcription factor, is up-regulated in cellular senescence. Cancer Sci 2007; 98: 1468-75.
103. Zindy F, Quelle DE, Roussel MF, Sherr CJ,. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 1997; 15: 203-11.
104. Tsygankov D, Liu Y, Sanoff HK, Sharpless NE, Elston TC,. A quantitative model for age-dependent expression of the p16INK4a tumor suppressor. Proc Natl Acad Sci USA 2009; 106: 16562-67.
105. Nielsen GP, Stemmer-Rachamimov AO, Shaw J, Roy JE, Koh J, Louis DN,. Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab Invest 1999; 79: 1137-43.
106. Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE,. p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 2006; 443: 453-57.
107. Chen J, Astle CM, Harrison DE,. Genetic regulation of primitive hematopoietic stem cell senescence. Exp Hematol 2000; 28: 442-50.
108. Conboy IM, Conboy MJ, Smythe G M, Rando TA,. Notch-mediated restoration of regenerative potential to aged muscle. Science 2003; 302: 1575-77.
109. Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ,. Bmi-1 dependence distinguishes neural stem cell selfrenewal from progenitor proliferation. Nature 2003; 425: 962-67.
110. Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Dürr P, Wlaschek M,. p16INK4Ais a robust in vivo biomarker of cellular aging in human skin. Aging Cell 2006; 5: 379-89.
111. Narita M, Nunez 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: 703-16.
112. Di Micco R, Sulli G, Dobreva M, Liontos M, Botrugno OA, Gargiulo G, dal Zuffo R, Matti V, d'Ario G, Montani E, Mercurio C, Hahn WC, et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nat Cell Biol 2011; 13: 292-302.
113. 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: 457-68.
114. Kim HJ, Kim K, Yu BP, Chung HY,. The effect of age on cyclooxygenases-2 gene expression: NF-KB activation and IKK degradation. Free Radic Biol Med 2000; 28: 683-92.
115. Haddad JJ,. Science review: redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for nuclear factor-kappa B. Crit Care 2002; 6: 481-90.
116. Handel ML, McMorrow LB, Gravallese EM,. Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. Arthritis Rheum 1995; 38: 1762-70.
117. Poynter ME, Daynes RA,. Peroxisome proliferatoractivated receptor activation modulates cellular redox status, represses nuclear factor-kB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 1998; 273: 32833-41.
118. Lee MY, Wang Y, Vanhoutte PM,. Senescence of cultured porcine coronary arterial endothelial cells is associated with accelerated oxidative stress and activation of NFK B. J Vas Res 2009; 47: 287-98.
119. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J,. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 2001; 11: 12072-7.
120. 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 fibrobalsts. Science 1997; 275: 1649-52.
121. Lee AC, Fenster BE, Ito H, Takeda K, Bae NS, Hirai T, Yu Ferrans VJ, Howard BH, Finkel T,. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J Biol Chem 1999; 274: 7936-40.
122. Rowland BD, Denissov SG, Douma S, Stunnenberg HG, Bernards R, Peeper DS,. E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest. Cancer Cell 2002; 2: 55-65.
123. Leong WF, Chau JF, Li B,. p53 Deficiency leads to compensatory up-regulation of p16INK4a. Mol Cancer Res 2009; 7: 354-60.
124. Su X, Cho MS, Gi YJ, Ayanga BA, Sherr CJ, Flores ER,. Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf. EMBO J 2009; 28: 1904-15.
125. Guarente L,. Sirtuins, aging, and medicine. N Engl J Med 2011; 364: 2235-44.