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Hallmarks for senescence in carcinogenesis: novel signaling players

  • Cell Death and Disease
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Abstract

Cellular senescence is a potent anti-cancer mechanism controlled by tumor suppressor genes, particularly p53 and pRb, which is characterized by the irreversible loss of proliferation. Senescence induced by DNA damage, oncogenic stimulation, or excessive mitogenic input, serves as a barrier that counteracts cancer progression. Emerging evidence in cellular and in in vivo models revealed the involvement of additional signaling players in senescence, including PML, CK2, Bcl-2, PI3K effectors such as Rheb, Rho small GTPases, and cytokines. Recent studies have also implicated protein kinase C (PKC) isozymes as modulators of senescence phenotypes and showed that phorbol esters, widely used PKC activators, can induce senescence in a number of cancer cells. These novel findings suggest a complex array of cross-talks between senescence pathways and may have significant implications in cancer therapy.

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References

  1. Bielas JH et al (2006) Human cancers express a mutator phenotype. Proc Natl Acad Sci USA 103(48):18238–18242. doi:10.1073/pnas.0607057103

    Article  PubMed  CAS  Google Scholar 

  2. Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396(6712):643–649. doi:10.1038/25292

    Article  PubMed  CAS  Google Scholar 

  3. Vogelstein B, Kinzler KW (1993) The multistep nature of cancer. Trends Genet 9(4):138–141. doi:10.1016/0168-9525(93)90209-Z

    Article  PubMed  CAS  Google Scholar 

  4. Knudson AG (1993) Antioncogenes and human cancer. Proc Natl Acad Sci USA 90(23):10914–10921. doi:10.1073/pnas.90.23.10914

    Article  PubMed  CAS  Google Scholar 

  5. Varmus HE (1984) The molecular genetics of cellular oncogenes. Annu Rev Genet 18:553–612. doi:10.1146/annurev.ge.18.120184.003005

    Article  PubMed  CAS  Google Scholar 

  6. Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10(8):789–799. doi:10.1038/nm1087

    Article  PubMed  CAS  Google Scholar 

  7. Shelton BP et al (2008) Epigenetic regulation of human epithelial cell cancers. Curr Opin Mol Ther 10(6):568–578

    PubMed  CAS  Google Scholar 

  8. Mountzios G, Fouret P, Soria JC (2008) Mechanisms of Disease: signal transduction in lung carcinogenesis—a comparison of smokers and never-smokers. Nat Clin Pract Oncol 5(10):610–618. doi:10.1038/ncponc1181

    Article  PubMed  CAS  Google Scholar 

  9. Stein GS et al (2008) Genetic and epigenetic regulation in nuclear microenvironments for biological control in cancer. J Cell Biochem 104(6):2016–2026. doi:10.1002/jcb.21813

    Article  PubMed  CAS  Google Scholar 

  10. Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120(4):513–522. doi:10.1016/j.cell.2005.02.003

    Article  PubMed  CAS  Google Scholar 

  11. Hickman ES, Moroni MC, Helin K (2002) The role of p53 and pRB in apoptosis and cancer. Curr Opin Genet Dev 12(1):60–66. doi:10.1016/S0959-437X(01)00265-9

    Article  PubMed  CAS  Google Scholar 

  12. Callegari AJ, Kelly TJ (2007) Shedding light on the DNA damage checkpoint. Cell Cycle 6(6):660–666

    PubMed  CAS  Google Scholar 

  13. Branzei D, Foiani M (2008) Regulation of DNA repair throughout the cell cycle. Nat Rev Mol Cell Biol 9(4):297–308. doi:10.1038/nrm2351

    Article  PubMed  CAS  Google Scholar 

  14. Lowe SW, Cepero E, Evan G (2004) Intrinsic tumour suppression. Nature 432(7015):307–315. doi:10.1038/nature03098

    Article  PubMed  CAS  Google Scholar 

  15. Roninson IB, Broude EV, Chang BD (2001) If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat 4(5):303–313. doi:10.1054/drup.2001.0213

    Article  PubMed  CAS  Google Scholar 

  16. Schmitt CA (2003) Senescence, apoptosis and therapy—cutting the lifelines of cancer. Nat Rev Cancer 3(4):286–295. doi:10.1038/nrc1044

    Article  PubMed  CAS  Google Scholar 

  17. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621. doi:10.1016/0014-4827(61)90192-6

    Article  Google Scholar 

  18. Shay JW, Roninson IB (2004) Hallmarks of senescence in carcinogenesis and cancer therapy. Oncogene 23(16):2919–2933. doi:10.1038/sj.onc.1207518

    Article  PubMed  CAS  Google Scholar 

  19. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8(9):729–740. doi:10.1038/nrm2233

    Article  PubMed  CAS  Google Scholar 

  20. Dimri GP (2005) What has senescence got to do with cancer? Cancer Cell 7(6):505–512. doi:10.1016/j.ccr.2005.05.025

    Article  PubMed  CAS  Google Scholar 

  21. d’Adda di Fagagna F et al (2003) A DNA damage checkpoint response in telomere-initiated senescence. Nature 426(6963):194–198

    Article  PubMed  CAS  Google Scholar 

  22. Takai H, Smogorzewska A, de Lange T (2003) DNA damage foci at dysfunctional telomeres. Curr Biol 13(17):1549–1556. doi:10.1016/S0960-9822(03)00542-6

    Article  PubMed  CAS  Google Scholar 

  23. Gire V et al (2004) DNA damage checkpoint kinase Chk2 triggers replicative senescence. EMBO J 23(13):2554–2563. doi:10.1038/sj.emboj.7600259

    Article  PubMed  CAS  Google Scholar 

  24. Herbig U et al (2004) Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Mol Cell 14(4):501–513. doi:10.1016/S1097-2765(04)00256-4

    Article  PubMed  CAS  Google Scholar 

  25. Dimri GP et al (2000) Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. Mol Cell Biol 20(1):273–285

    Article  PubMed  CAS  Google Scholar 

  26. Lin AW et al (1998) Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev 12(19):3008–3019. doi:10.1101/gad.12.19.3008

    Article  PubMed  CAS  Google Scholar 

  27. Michaloglou C et al (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436(7051):720–724. doi:10.1038/nature03890

    Article  PubMed  CAS  Google Scholar 

  28. Serrano M et al (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88(5):593–602. doi:10.1016/S0092-8674(00)81902-9

    Article  PubMed  CAS  Google Scholar 

  29. Shay JW, Wright WE (2002) Telomerase: a target for cancer therapeutics. Cancer Cell 2(4):257–265. doi:10.1016/S1535-6108(02)00159-9

    Article  PubMed  CAS  Google Scholar 

  30. Zhu J et al (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12(19):2997–3007. doi:10.1101/gad.12.19.2997

    Article  PubMed  CAS  Google Scholar 

  31. Bartek J, Bartkova J, Lukas J (2007) DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26(56):7773–7779. doi:10.1038/sj.onc.1210881

    Article  PubMed  CAS  Google Scholar 

  32. Bartkova J et al (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444(7119):633–637. doi:10.1038/nature05268

    Article  PubMed  CAS  Google Scholar 

  33. Braig M et al (2005) Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436(7051):660–665. doi:10.1038/nature03841

    Article  PubMed  CAS  Google Scholar 

  34. Campisi J (2005) Suppressing cancer: the importance of being senescent. Science 309(5736):886–887. doi:10.1126/science.1116801

    Article  PubMed  CAS  Google Scholar 

  35. Chen Z et al (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436(7051):725–730. doi:10.1038/nature03918

    Article  PubMed  CAS  Google Scholar 

  36. Collado M et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436(7051):642. doi:10.1038/436642a

    Article  PubMed  CAS  Google Scholar 

  37. Gewirtz DA, Holt SE, Elmore LW (2008) Accelerated senescence: an emerging role in tumor cell response to chemotherapy and radiation. Biochem Pharmacol 76(8):947–957. doi:10.1016/j.bcp.2008.06.024

    Article  PubMed  CAS  Google Scholar 

  38. Roberson RS et al (2005) Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. Cancer Res 65(7):2795–2803. doi:10.1158/0008-5472.CAN-04-1270

    Article  PubMed  CAS  Google Scholar 

  39. te Poele RH et al (2002) DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res 62(6):1876–1883

    PubMed  CAS  Google Scholar 

  40. Schmitt CA et al (2002) A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109(3):335–346. doi:10.1016/S0092-8674(02)00734-1

    Article  PubMed  CAS  Google Scholar 

  41. Ventura A et al (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445(7128):661–665. doi:10.1038/nature05541

    Article  PubMed  CAS  Google Scholar 

  42. Xue W et al (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445(7128):656–660. doi:10.1038/nature05529

    Article  PubMed  CAS  Google Scholar 

  43. Chang BD et al (2002) Molecular determinants of terminal growth arrest induced in tumor cells by a chemotherapeutic agent. Proc Natl Acad Sci USA 99(1):389–394. doi:10.1073/pnas.012602599

    Article  PubMed  CAS  Google Scholar 

  44. Dokmanovic M et al (2002) Retinoid-induced growth arrest of breast carcinoma cells involves co-activation of multiple growth-inhibitory genes. Cancer Biol Ther 1(1):24–27

    PubMed  CAS  Google Scholar 

  45. Suzuki T et al (2001) Induction of senescence-associated genes by 5-bromodeoxyuridine in HeLa cells. Exp Gerontol 36(3):465–474. doi:10.1016/S0531-5565(00)00223-0

    Article  PubMed  CAS  Google Scholar 

  46. Krtolica A et al (2001) Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA 98(21):12072–12077. doi:10.1073/pnas.211053698

    Article  PubMed  CAS  Google Scholar 

  47. Komarova EA et al (1998) Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53. Oncogene 17(9):1089–1096. doi:10.1038/sj.onc.1202303

    Article  PubMed  CAS  Google Scholar 

  48. Soengas MS (2008) Cancer: ins and outs of tumour control. Nature 454(7204):586–587. doi:10.1038/454586a

    Article  PubMed  CAS  Google Scholar 

  49. Lu X (2005) p53: a heavily dictated dictator of life and death. Curr Opin Genet Dev 15(1):27–33. doi:10.1016/j.gde.2004.12.008

    Article  PubMed  CAS  Google Scholar 

  50. Bischof O, Nacerddine K, Dejean A (2005) Human papillomavirus oncoprotein E7 targets the promyelocytic leukemia protein and circumvents cellular senescence via the Rb and p53 tumor suppressor pathways. Mol Cell Biol 25(3):1013–1024. doi:10.1128/MCB.25.3.1013-1024.2005

    Article  PubMed  CAS  Google Scholar 

  51. Ferbeyre G et al (2000) PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14(16):2015–2027

    PubMed  CAS  Google Scholar 

  52. Garkavtsev I, Riabowol K (1997) Extension of the replicative life span of human diploid fibroblasts by inhibition of the p33ING1 candidate tumor suppressor. Mol Cell Biol 17(4):2014–2019

    PubMed  CAS  Google Scholar 

  53. Goeman F et al (2005) Growth inhibition by the tumor suppressor p33ING1 in immortalized and primary cells: involvement of two silencing domains and effect of Ras. Mol Cell Biol 25(1):422–431. doi:10.1128/MCB.25.1.422-431.2005

    Article  PubMed  CAS  Google Scholar 

  54. Lowe SW, Sherr CJ (2003) Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 13(1):77–83. doi:10.1016/S0959-437X(02)00013-8

    Article  PubMed  CAS  Google Scholar 

  55. Mallette FA et al (2004) Human fibroblasts require the Rb family of tumor suppressors, but not p53, for PML-induced senescence. Oncogene 23(1):91–99. doi:10.1038/sj.onc.1206886

    Article  PubMed  CAS  Google Scholar 

  56. Wright WE, Shay JW (2002) Historical claims and current interpretations of replicative aging. Nat Biotechnol 20(7):682–688. doi:10.1038/nbt0702-682

    Article  PubMed  CAS  Google Scholar 

  57. Salomoni P, Pandolfi PP (2002) The role of PML in tumor suppression. Cell 108(2):165–170. doi:10.1016/S0092-8674(02)00626-8

    Article  PubMed  CAS  Google Scholar 

  58. Pearson M, Pelicci PG (2001) PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene 20(49):7250–7256. doi:10.1038/sj.onc.1204856

    Article  PubMed  CAS  Google Scholar 

  59. Pearson M et al (2000) PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406(6792):207–210. doi:10.1038/35018127

    Article  PubMed  CAS  Google Scholar 

  60. de Stanchina E et al (2004) PML is a direct p53 target that modulates p53 effector functions. Mol Cell 13(4):523–535. doi:10.1016/S1097-2765(04)00062-0

    Article  PubMed  Google Scholar 

  61. Khan MM et al (2001) Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Mol Cell 7(6):1233–1243. doi:10.1016/S1097-2765(01)00257-X

    Article  PubMed  CAS  Google Scholar 

  62. Khan MM et al (2001) PML-RARalpha alleviates the transcriptional repression mediated by tumor suppressor Rb. J Biol Chem 276(47):43491–43494. doi:10.1074/jbc.C100532200

    Article  PubMed  CAS  Google Scholar 

  63. Guo A et al (2000) The function of PML in p53-dependent apoptosis. Nat Cell Biol 2(10):730–736. doi:10.1038/35036365

    Article  PubMed  CAS  Google Scholar 

  64. Adams JM et al (1985) The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318(6046):533–538. doi:10.1038/318533a0

    Article  PubMed  CAS  Google Scholar 

  65. Schmitt CA et al (1999) INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev 13(20):2670–2677. doi:10.1101/gad.13.20.2670

    Article  PubMed  CAS  Google Scholar 

  66. Seker H et al (2003) UV-C-induced DNA damage leads to p53-dependent nuclear trafficking of PML. Oncogene 22(11):1620–1628. doi:10.1038/sj.onc.1206140

    Article  PubMed  CAS  Google Scholar 

  67. Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12(5):226–230. doi:10.1016/S0962-8924(02)02279-1

    Article  PubMed  CAS  Google Scholar 

  68. Kato K et al (2002) Molecular cloning of the wheat CK2alpha gene and detection of its linkage with Vrn-A1 on chromosome 5A. Theor Appl Genet 104(6–7):1071–1077. doi:10.1007/s00122-001-0805-0

    PubMed  CAS  Google Scholar 

  69. Litchfield DW (2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 369(Pt 1):1–15. doi:10.1042/BJ20021469

    Article  PubMed  CAS  Google Scholar 

  70. Landesman-Bollag E et al (2001) Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20(25):3247–3257. doi:10.1038/sj.onc.1204411

    Article  PubMed  CAS  Google Scholar 

  71. Landesman-Bollag E et al (2001) Protein kinase CK2: signaling and tumorigenesis in the mammary gland. Mol Cell Biochem 227(1–2):153–165. doi:10.1023/A:1013108822847

    Article  PubMed  CAS  Google Scholar 

  72. Bruins W et al (2004) Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol Cell Biol 24(20):8884–8894. doi:10.1128/MCB.24.20.8884-8894.2004

    Article  PubMed  CAS  Google Scholar 

  73. Keller DM et al (2001) A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell 7(2):283–292. doi:10.1016/S1097-2765(01)00176-9

    Article  PubMed  CAS  Google Scholar 

  74. Schuster N et al (2001) Wild-type p53 inhibits protein kinase CK2 activity. J Cell Biochem 81(1):172–183. doi:10.1002/1097-4644(20010401)81:1<;172::AID-JCB1033>;3.0.CO;2-O

    Article  PubMed  CAS  Google Scholar 

  75. Scaglioni PP et al (2006) A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126(2):269–283. doi:10.1016/j.cell.2006.05.041

    Article  PubMed  CAS  Google Scholar 

  76. Ryu SJ et al (2006) Role of Src-specific phosphorylation site on focal adhesion kinase for senescence-associated apoptosis resistance. Apoptosis 11(3):303–313. doi:10.1007/s10495-006-3978-9

    Article  PubMed  CAS  Google Scholar 

  77. Ryu SJ, Oh YS, Park SC (2007) Failure of stress-induced downregulation of Bcl-2 contributes to apoptosis resistance in senescent human diploid fibroblasts. Cell Death Differ 14(5):1020–1028

    PubMed  CAS  Google Scholar 

  78. Seluanov A et al (2001) Change of the death pathway in senescent human fibroblasts in response to DNA damage is caused by an inability to stabilize p53. Mol Cell Biol 21(5):1552–1564. doi:10.1128/MCB.21.5.1552-1564.2001

    Article  PubMed  CAS  Google Scholar 

  79. Yeo EJ et al (2000) Reduction of UV-induced cell death in the human senescent fibroblasts. Mol Cells 10(4):415–422

    PubMed  CAS  Google Scholar 

  80. Wang E (1995) Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res 55(11):2284–2292

    PubMed  CAS  Google Scholar 

  81. Bladier C et al (1997) Response of a primary human fibroblast cell line to H2O2: senescence-like growth arrest or apoptosis? Cell Growth Differ 8(5):589–598

    PubMed  CAS  Google Scholar 

  82. Chen QM, Liu J, Merrett JB (2000) Apoptosis or senescence-like growth arrest: influence of cell-cycle position, p53, p21 and bax in H2O2 response of normal human fibroblasts. Biochem J 347(Pt 2):543–551. doi:10.1042/0264-6021:3470543

    Article  PubMed  CAS  Google Scholar 

  83. Chen CL et al (2006) Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis. Mol Pharmacol 70(2):510–517. doi:10.1124/mol.106.024059

    Article  PubMed  CAS  Google Scholar 

  84. Kim HS et al (2003) Constitutive induction of p-Erk1/2 accompanied by reduced activities of protein phosphatases 1 and 2A and MKP3 due to reactive oxygen species during cellular senescence. J Biol Chem 278(39):37497–37510. doi:10.1074/jbc.M211739200

    Article  PubMed  CAS  Google Scholar 

  85. Li L et al (2003) Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Mol Cell Biol 23(24):9389–9404. doi:10.1128/MCB.23.24.9389-9404.2003

    Article  PubMed  CAS  Google Scholar 

  86. Tombor B, Rundell K, Oltvai ZN (2003) Bcl-2 promotes premature senescence induced by oncogenic Ras. Biochem Biophys Res Commun 303(3):800–807. doi:10.1016/S0006-291X(03)00402-9

    Article  PubMed  CAS  Google Scholar 

  87. Crescenzi E, Palumbo G, Brady HJ (2003) Bcl-2 activates a programme of premature senescence in human carcinoma cells. Biochem J 375(Pt 2):263–274. doi:10.1042/BJ20030868

    Article  PubMed  CAS  Google Scholar 

  88. Schmitt CA et al (2002) Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1(3):289–298. doi:10.1016/S1535-6108(02)00047-8

    Article  PubMed  CAS  Google Scholar 

  89. Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109(3):321–334. doi:10.1016/S0092-8674(02)00738-9

    Article  PubMed  CAS  Google Scholar 

  90. Strasser A et al (1990) Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2. Nature 348(6299):331–333. doi:10.1038/348331a0

    Article  PubMed  CAS  Google Scholar 

  91. Eischen CM et al (2001) Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol 21(22):7653–7662. doi:10.1128/MCB.21.22.7653-7662.2001

    Article  PubMed  CAS  Google Scholar 

  92. Hermeking H, Eick D (1994) Mediation of c-Myc-induced apoptosis by p53. Science 265(5181):2091–2093. doi:10.1126/science.8091232

    Article  PubMed  CAS  Google Scholar 

  93. Zindy F et al (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12(15):2424–2433. doi:10.1101/gad.12.15.2424

    Article  PubMed  CAS  Google Scholar 

  94. Marzo I et al (1998) Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281(5385):2027–2031. doi:10.1126/science.281.5385.2027

    Article  PubMed  CAS  Google Scholar 

  95. Shimizu S et al (1996) Bcl-2 blocks loss of mitochondrial membrane potential while ICE inhibitors act at a different step during inhibition of death induced by respiratory chain inhibitors. Oncogene 13(1):21–29

    PubMed  CAS  Google Scholar 

  96. Das A et al (2004) Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities. Mol Cancer 3(1):36. doi:10.1186/1476-4598-3-36

    Article  PubMed  CAS  Google Scholar 

  97. Hagen TM et al (1997) Mitochondrial decay in hepatocytes from old rats: membrane potential declines, heterogeneity and oxidants increase. Proc Natl Acad Sci USA 94(7):3064–3069. doi:10.1073/pnas.94.7.3064

    Article  PubMed  CAS  Google Scholar 

  98. Martinez AO et al (1991) Separation of two subpopulations of old human fibroblasts by mitochondria (rhodamine 123) fluorescence. Growth Dev Aging 55(3):185–191

    PubMed  CAS  Google Scholar 

  99. Rottenberg H, Wu S (1997) Mitochondrial dysfunction in lymphocytes from old mice: enhanced activation of the permeability transition. Biochem Biophys Res Commun 240(1):68–74. doi:10.1006/bbrc.1997.7605

    Article  PubMed  CAS  Google Scholar 

  100. Hall A (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33(Pt 5):891–895. doi:10.1042/BST20050891

    PubMed  CAS  Google Scholar 

  101. Schmitz AA et al (2000) Rho GTPases: signaling, migration, and invasion. Exp Cell Res 261(1):1–12. doi:10.1006/excr.2000.5049

    Article  PubMed  CAS  Google Scholar 

  102. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420(6916):629–635. doi:10.1038/nature01148

    Article  PubMed  CAS  Google Scholar 

  103. Price LS, Collard JG (2001) Regulation of the cytoskeleton by Rho-family GTPases: implications for tumour cell invasion. Semin Cancer Biol 11(2):167–173. doi:10.1006/scbi.2000.0367

    Article  PubMed  CAS  Google Scholar 

  104. Aznar S, Lacal JC (2001) Rho signals to cell growth and apoptosis. Cancer Lett 165(1):1–10. doi:10.1016/S0304-3835(01)00412-8

    Article  PubMed  CAS  Google Scholar 

  105. Bar-Sagi D, Hall A (2000) Ras and Rho GTPases: a family reunion. Cell 103(2):227–238. doi:10.1016/S0092-8674(00)00115-X

    Article  PubMed  CAS  Google Scholar 

  106. Zohn IM et al (1998) Rho family proteins and Ras transformation: the RHOad less traveled gets congested. Oncogene 17(11 Reviews):1415–1438

    Article  PubMed  CAS  Google Scholar 

  107. Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett 171(1):1–10. doi:10.1016/S0304-3835(01)00528-6

    Article  PubMed  CAS  Google Scholar 

  108. Minard ME et al (2005) The guanine nucleotide exchange factor Tiam1 increases colon carcinoma growth at metastatic sites in an orthotopic nude mouse model. Oncogene 24(15):2568–2573. doi:10.1038/sj.onc.1208503

    Article  PubMed  CAS  Google Scholar 

  109. Katzav S (2007) Flesh and blood: the story of Vav1, a gene that signals in hematopoietic cells but can be transforming in human malignancies. Cancer Lett 255(2):241–254. doi:10.1016/j.canlet.2007.04.015

    Article  PubMed  CAS  Google Scholar 

  110. Faried A et al (2007) Clinical and prognostic significance of RhoA and RhoC gene expression in esophageal squamous cell carcinoma. Ann Surg Oncol 14(12):3593–3601. doi:10.1245/s10434-007-9562-x

    Article  PubMed  Google Scholar 

  111. Engers R et al (2007) Prognostic relevance of increased Rac GTPase expression in prostate carcinomas. Endocr Relat Cancer 14(2):245–256. doi:10.1677/ERC-06-0036

    Article  PubMed  CAS  Google Scholar 

  112. Zhang C et al (2007) Overexpression of RhoE has a prognostic value in non-small cell lung cancer. Ann Surg Oncol 14(9):2628–2635. doi:10.1245/s10434-007-9457-x

    Article  PubMed  Google Scholar 

  113. Kamai T et al (2004) Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 10(14):4799–4805. doi:10.1158/1078-0432.CCR-0436-03

    Article  PubMed  CAS  Google Scholar 

  114. Pan Y et al (2004) Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun 315(3):686–691. doi:10.1016/j.bbrc.2004.01.108

    Article  PubMed  CAS  Google Scholar 

  115. Coleman ML, Marshall CJ, Olson MF (2004) RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol 5(5):355–366. doi:10.1038/nrm1365

    Article  PubMed  CAS  Google Scholar 

  116. Moore KA et al (1997) Rac1 is required for cell proliferation and G2/M progression. Biochem J 326(Pt 1):17–20

    PubMed  CAS  Google Scholar 

  117. Cho KA et al (2004) Morphological adjustment of senescent cells by modulating caveolin-1 status. J Biol Chem 279(40):42270–42278. doi:10.1074/jbc.M402352200

    Article  PubMed  CAS  Google Scholar 

  118. Alexander K, Yang HS, Hinds PW (2004) Cellular senescence requires CDK5 repression of Rac1 activity. Mol Cell Biol 24(7):2808–2819. doi:10.1128/MCB.24.7.2808-2819.2004

    Article  PubMed  CAS  Google Scholar 

  119. Ridley AJ (2001) Rho family proteins: coordinating cell responses. Trends Cell Biol 11(12):471–477. doi:10.1016/S0962-8924(01)02153-5

    Article  PubMed  CAS  Google Scholar 

  120. Yang HS, Hinds PW (2006) Phosphorylation of ezrin by cyclin-dependent kinase 5 induces the release of Rho GDP dissociation inhibitor to inhibit Rac1 activity in senescent cells. Cancer Res 66(5):2708–2715. doi:10.1158/0008-5472.CAN-05-3141

    Article  PubMed  CAS  Google Scholar 

  121. Yang HS, Hinds PW (2003) Increased ezrin expression and activation by CDK5 coincident with acquisition of the senescent phenotype. Mol Cell 11(5):1163–1176. doi:10.1016/S1097-2765(03)00135-7

    Article  PubMed  CAS  Google Scholar 

  122. Debidda M, Williams DA, Zheng Y (2006) Rac1 GTPase regulates cell genomic stability and senescence. J Biol Chem 281(50):38519–38528. doi:10.1074/jbc.M604607200

    Article  PubMed  CAS  Google Scholar 

  123. Cammarano MS et al (2005) Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling. Mol Cell Biol 25(21):9532–9542. doi:10.1128/MCB.25.21.9532-9542.2005

    Article  PubMed  CAS  Google Scholar 

  124. Frippiat C et al (2001) Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts. J Biol Chem 276(4):2531–2537. doi:10.1074/jbc.M006809200

    Article  PubMed  CAS  Google Scholar 

  125. Frippiat C et al (2002) Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts. Free Radic Biol Med 33(10):1334–1346. doi:10.1016/S0891-5849(02)01044-4

    Article  PubMed  CAS  Google Scholar 

  126. Chretien A et al (2008) Role of TGF-beta1-independent changes in protein neosynthesis, p38alphaMAPK, and cdc42 in hydrogen peroxide-induced senescence-like morphogenesis. Free Radic Biol Med 44(9):1732–1751. doi:10.1016/j.freeradbiomed.2008.01.026

    Article  PubMed  CAS  Google Scholar 

  127. Wang L et al (2007) Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes. Proc Natl Acad Sci USA 104(4):1248–1253. doi:10.1073/pnas.0609149104

    Article  PubMed  CAS  Google Scholar 

  128. Kortlever RM et al (2008) Suppression of the p53-dependent replicative senescence response by lysophosphatidic acid signaling. Mol Cancer Res 6(9):1452–1460. doi:10.1158/1541-7786.MCR-08-0066

    Article  PubMed  CAS  Google Scholar 

  129. Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100(4):387–390. doi:10.1016/S0092-8674(00)80674-1

    Article  PubMed  CAS  Google Scholar 

  130. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12(1):9–22. doi:10.1016/j.ccr.2007.05.008

    Article  PubMed  CAS  Google Scholar 

  131. Manning BD, Cantley LC (2003) Rheb fills a GAP between TSC and TOR. Trends Biochem Sci 28(11):573–576. doi:10.1016/j.tibs.2003.09.003

    Article  PubMed  CAS  Google Scholar 

  132. Li Y et al (2004) TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci 29(1):32–38. doi:10.1016/j.tibs.2003.11.007

    Article  PubMed  CAS  Google Scholar 

  133. Bai X et al (2007) Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 318(5852):977–980. doi:10.1126/science.1147379

    Article  PubMed  CAS  Google Scholar 

  134. Mavrakis KJ et al (2008) Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev 22(16):2178–2188. doi:10.1101/gad.1690808

    Article  PubMed  CAS  Google Scholar 

  135. Nardella C et al (2008) Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Genes Dev 22(16):2172–2177. doi:10.1101/gad.1699608

    Article  PubMed  CAS  Google Scholar 

  136. Wendel HG et al (2007) Dissecting eIF4E action in tumorigenesis. Genes Dev 21(24):3232–3237. doi:10.1101/gad.1604407

    Article  PubMed  CAS  Google Scholar 

  137. Ruggero D et al (2004) The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 10(5):484–486. doi:10.1038/nm1042

    Article  PubMed  CAS  Google Scholar 

  138. Bernardi R et al (2006) PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442(7104):779–785. doi:10.1038/nature05029

    Article  PubMed  CAS  Google Scholar 

  139. Schewe DM, Aguirre-Ghiso JA (2008) ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci USA 105(30):10519–10524. doi:10.1073/pnas.0800939105

    Article  PubMed  CAS  Google Scholar 

  140. Dhomen N, Marais R (2007) New insight into BRAF mutations in cancer. Curr Opin Genet Dev 17(1):31–39. doi:10.1016/j.gde.2006.12.005

    Article  PubMed  CAS  Google Scholar 

  141. Davies H et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954. doi:10.1038/nature00766

    Article  PubMed  CAS  Google Scholar 

  142. Bennett DC (2003) Human melanocyte senescence and melanoma susceptibility genes. Oncogene 22(20):3063–3069. doi:10.1038/sj.onc.1206446

    Article  PubMed  CAS  Google Scholar 

  143. Pollock PM et al (2003) High frequency of BRAF mutations in nevi. Nat Genet 33(1):19–20. doi:10.1038/ng1054

    Article  PubMed  CAS  Google Scholar 

  144. Wajapeyee N et al (2008) Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132(3):363–374. doi:10.1016/j.cell.2007.12.032

    Article  PubMed  CAS  Google Scholar 

  145. Kuilman T et al (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133(6):1019–1031. doi:10.1016/j.cell.2008.03.039

    Article  PubMed  CAS  Google Scholar 

  146. Acosta JC et al (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133(6):1006–1018. doi:10.1016/j.cell.2008.03.038

    Article  PubMed  CAS  Google Scholar 

  147. Griner EM, Kazanietz MG (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7(4):281. doi:10.1038/nrc2110

    Article  PubMed  CAS  Google Scholar 

  148. Castagna M et al (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem 257(13):7847–7851

    PubMed  CAS  Google Scholar 

  149. Mellor H, Parker PJ (1998) The extended protein kinase C superfamily. Biochem J 332(Pt 2):281–292

    PubMed  CAS  Google Scholar 

  150. Detjen KM et al (2000) Activation of protein kinase Calpha inhibits growth of pancreatic cancer cells via p21(cip)-mediated G(1) arrest. J Cell Sci 113(Pt 17):3025–3035

    PubMed  CAS  Google Scholar 

  151. Frey MR et al (2000) Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium. J Cell Biol 151(4):763–778. doi:10.1083/jcb.151.4.763

    Article  PubMed  CAS  Google Scholar 

  152. Sun XG, Rotenberg SA (1999) Overexpression of protein kinase Calpha in MCF-10A human breast cells engenders dramatic alterations in morphology, proliferation, and motility. Cell Growth Differ 10(5):343–352

    PubMed  CAS  Google Scholar 

  153. Jiang XH et al (2004) Antisense targeting protein kinase C alpha and beta1 inhibits gastric carcinogenesis. Cancer Res 64(16):5787–5794. doi:10.1158/0008-5472.CAN-03-1172

    Article  PubMed  CAS  Google Scholar 

  154. Sharma GD, Kakazu A, Bazan HE (2007) Protein kinase C alpha and epsilon differentially modulate hepatocyte growth factor-induced epithelial proliferation and migration. Exp Eye Res 85(2):289–297. doi:10.1016/j.exer.2007.05.004

    Article  PubMed  CAS  Google Scholar 

  155. Wu TT et al (2008) Reduction of PKC alpha decreases cell proliferation, migration, and invasion of human malignant hepatocellular carcinoma. J Cell Biochem 103(1):9–20. doi:10.1002/jcb.21378

    Article  PubMed  CAS  Google Scholar 

  156. Mischak H et al (1993) Overexpression of protein kinase C-delta and -epsilon in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J Biol Chem 268(9):6090–6096

    PubMed  CAS  Google Scholar 

  157. Perletti GP et al (1996) Overexpression of protein kinase C epsilon is oncogenic in rat colonic epithelial cells. Oncogene 12(4):847–854

    PubMed  CAS  Google Scholar 

  158. Perletti GP et al (1999) PKCdelta acts as a growth and tumor suppressor in rat colonic epithelial cells. Oncogene 18(5):1251–1256. doi:10.1038/sj.onc.1202408

    Article  PubMed  CAS  Google Scholar 

  159. Fishman DD, Segal S, Livneh E (1998) The role of protein kinase C in G1 and G2/M phases of the cell cycle. Int J Oncol 12(1):181–186 Review

    PubMed  CAS  Google Scholar 

  160. Black JD (2000) Protein kinase C-mediated regulation of the cell cycle. Front Biosci 5:D406–D423. doi:10.2741/Black

    Article  PubMed  CAS  Google Scholar 

  161. Nakagawa M et al (2005) Phorbol Ester-induced G1 Phase Arrest Selectively Mediated by Protein Kinase C{delta}-dependent Induction of p21. J Biol Chem 280(40):33926–33934. doi:10.1074/jbc.M505748200

    Article  PubMed  CAS  Google Scholar 

  162. Gonzalez-Guerrico AM, Kazanietz MG (2005) Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade: a key role for protein kinase C delta. J Biol Chem 280(47):38982–38991. doi:10.1074/jbc.M506767200

    Article  PubMed  CAS  Google Scholar 

  163. Gonzalez-Guerrico AM et al (2005) Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells. J Biochem Mol Biol 38(6):639–645

    PubMed  CAS  Google Scholar 

  164. Brodie C, Blumberg PM (2003) Regulation of cell apoptosis by protein kinase c delta. Apoptosis 8(1):19–27. doi:10.1023/A:1021640817208

    Article  PubMed  CAS  Google Scholar 

  165. Bae KM et al (2007) Protein kinase C epsilon is overexpressed in primary human non-small cell lung cancers and functionally required for proliferation of non-small cell lung cancer cells in a p21/Cip1-dependent manner. Cancer Res 67(13):6053–6063. doi:10.1158/0008-5472.CAN-06-4037

    Article  PubMed  CAS  Google Scholar 

  166. Schonwasser DC et al (1998) Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol 18(2):790–798

    PubMed  CAS  Google Scholar 

  167. Slupsky JR et al (2007) Central role of protein kinase Cepsilon in constitutive activation of ERK1/2 and Rac1 in the malignant cells of hairy cell leukemia. Am J Pathol 170(2):745–754. doi:10.2353/ajpath.2007.060557

    Article  PubMed  CAS  Google Scholar 

  168. Ding L et al (2002) Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. J Biol Chem 277(38):35305–35313. doi:10.1074/jbc.M201460200

    Article  PubMed  CAS  Google Scholar 

  169. Lu D, Huang J, Basu A (2006) Protein kinase C{epsilon} activates protein kinase B/Akt via DNA-PK to protect against tumor necrosis factor-{alpha}-induced cell death. J Biol Chem 281(32):22799–22807. doi:10.1074/jbc.M603390200

    Article  PubMed  CAS  Google Scholar 

  170. McJilton MA et al (2003) Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells. Oncogene 22(39):7958–7968. doi:10.1038/sj.onc.1206795

    Article  PubMed  CAS  Google Scholar 

  171. Okhrimenko H et al (2005) Protein kinase C-epsilon regulates the apoptosis and survival of glioma cells. Cancer Res 65(16):7301–7309. doi:10.1158/0008-5472.CAN-05-1064

    Article  PubMed  CAS  Google Scholar 

  172. Pan Q et al (2006) Targeted disruption of protein kinase C{varepsilon} reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. Cancer Res 66(19):9379–9384. doi:10.1158/0008-5472.CAN-06-2646

    Article  PubMed  CAS  Google Scholar 

  173. Jansen AP et al (2001) Protein kinase C-epsilon transgenic mice: a unique model for metastatic squamous cell carcinoma. Cancer Res 61(3):808–812

    PubMed  CAS  Google Scholar 

  174. Tachado SD et al (2002) Regulation of tumor invasion and metastasis in protein kinase C epsilon-transformed NIH3T3 fibroblasts. J Cell Biochem 85(4):785–797. doi:10.1002/jcb.10164

    Article  PubMed  CAS  Google Scholar 

  175. Wu D et al (2002) Protein kinase C{epsilon} has the potential to advance the recurrence of human prostate cancer. Cancer Res 62(8):2423–2429

    PubMed  CAS  Google Scholar 

  176. Wheaton K, Riabowol K (2004) Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response factor. Mol Cell Biol 24(16):7298–7311. doi:10.1128/MCB.24.16.7298-7311.2004

    Article  PubMed  CAS  Google Scholar 

  177. Takahashi A et al (2006) Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 8(11):1291–1297. doi:10.1038/ncb1491

    Article  PubMed  CAS  Google Scholar 

  178. Lloyd AC (2002) Limits to lifespan. Nat Cell Biol 4(2):E25–E27. doi:10.1038/ncb0202-e25

    Article  PubMed  CAS  Google Scholar 

  179. Mathon NF et al (2001) Lack of replicative senescence in normal rodent glia. Science 291(5505):872–875. doi:10.1126/science.1056782

    Article  PubMed  CAS  Google Scholar 

  180. Ramirez RD et al (2001) Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev 15(4):398–403. doi:10.1101/gad.859201

    Article  PubMed  CAS  Google Scholar 

  181. Satyanarayana A et al (2004) Mitogen stimulation cooperates with telomere shortening to activate DNA damage responses and senescence signaling. Mol Cell Biol 24(12):5459–5474. doi:10.1128/MCB.24.12.5459-5474.2004

    Article  PubMed  CAS  Google Scholar 

  182. Cozzi SJ et al (2006) Induction of senescence in diterpene ester-treated melanoma cells via protein kinase C-dependent hyperactivation of the mitogen-activated protein kinase pathway. Cancer Res 66(20):10083–10091. doi:10.1158/0008-5472.CAN-06-0348

    Article  PubMed  CAS  Google Scholar 

  183. Ogbourne SM et al (2004) Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 64(8):2833–2839. doi:10.1158/0008-5472.CAN-03-2837

    Article  PubMed  CAS  Google Scholar 

  184. Castellano M et al (1997) CDKN2A/p16 is inactivated in most melanoma cell lines. Cancer Res 57(21):4868–4875

    PubMed  CAS  Google Scholar 

  185. Han ZT et al (1998) 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increase in depressed white blood cell counts in patients treated with cytotoxic cancer chemotherapeutic drugs. Proc Natl Acad Sci USA 95(9):5362–5365. doi:10.1073/pnas.95.9.5362

    Article  PubMed  CAS  Google Scholar 

  186. Han ZT et al (1998) Effect of intravenous infusions of 12-O-tetradecanoylphorbol-13-acetate (TPA) in patients with myelocytic leukemia: preliminary studies on therapeutic efficacy and toxicity. Proc Natl Acad Sci USA 95(9):5357–5361. doi:10.1073/pnas.95.9.5357

    Article  PubMed  CAS  Google Scholar 

  187. Cragg LH et al (2002) Phase I trial and correlative laboratory studies of bryostatin 1 (NSC 339555) and high-dose 1-B-d-arabinofuranosylcytosine in patients with refractory acute leukemia. Clin Cancer Res 8(7):2123–2133

    PubMed  CAS  Google Scholar 

  188. Haas NB et al (2003) Weekly bryostatin-1 in metastatic renal cell carcinoma: a phase II study. Clin Cancer Res 9(1):109–114

    PubMed  CAS  Google Scholar 

  189. Varterasian ML et al (2000) Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Clin Cancer Res 6(3):825–828

    PubMed  CAS  Google Scholar 

  190. Oliva JL et al (2008) S-phase-specific activation of PKC alpha induces senescence in non-small cell lung cancer cells. J Biol Chem 283(9):5466–5476. doi:10.1074/jbc.M707576200

    Article  PubMed  CAS  Google Scholar 

  191. Marquez VE, Blumberg PM (2003) Synthetic diacylglycerols (DAG) and DAG-lactones as activators of protein kinase C (PK-C). Acc Chem Res 36(6):434–443. doi:10.1021/ar020124b

    Article  PubMed  CAS  Google Scholar 

  192. Deng WG et al (2007) Synergistic tumor suppression by coexpression of FUS1 and p53 is associated with down-regulation of murine double minute-2 and activation of the apoptotic protease-activating factor 1-dependent apoptotic pathway in human non-small cell lung cancer cells. Cancer Res 67(2):709–717. doi:10.1158/0008-5472.CAN-06-3463

    Article  PubMed  CAS  Google Scholar 

  193. Khan QA, Anderson LM (2001) Hydrocarbon carcinogens evade cellular defense mechanism of G1 arrest in nontransformed and malignant lung cell lines. Toxicol Appl Pharmacol 173(2):105–113. doi:10.1006/taap.2001.9172

    Article  PubMed  CAS  Google Scholar 

  194. Zou CP et al (1998) Higher potency of N-(4-hydroxyphenyl)retinamide than all-trans-retinoic acid in induction of apoptosis in non-small cell lung cancer cell lines. Clin Cancer Res 4(5):1345–1355

    PubMed  CAS  Google Scholar 

  195. Lahn M et al (2004) Expression levels of protein kinase C-alpha in non-small-cell lung cancer. Clin Lung Cancer 6(3):184–189. doi:10.3816/CLC.2004.n.032

    Article  PubMed  CAS  Google Scholar 

  196. Ohtani N et al (2001) Opposing effects of Ets and Id proteins on p16INK4a expression during cellular senescence. Nature 409(6823):1067–1070. doi:10.1038/35059131

    Article  PubMed  CAS  Google Scholar 

  197. Liebermann DA, Hoffman B (2008) Gadd45 in stress signaling. J Mol Signal 3:15. doi:10.1186/1750-2187-3-15

    Article  PubMed  CAS  Google Scholar 

  198. Sheikh MS, Hollander MC, Fornance AJ Jr (2000) Role of Gadd45 in apoptosis. Biochem Pharmacol 59(1):43–45. doi:10.1016/S0006-2952(99)00291-9

    Article  PubMed  CAS  Google Scholar 

  199. Wang XW et al (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96(7):3706–3711. doi:10.1073/pnas.96.7.3706

    Article  PubMed  CAS  Google Scholar 

  200. Ythier D et al (2008) The new tumor suppressor genes ING: genomic structure and status in cancer. Int J Cancer 123(7):1483–1490. doi:10.1002/ijc.23790

    Article  PubMed  CAS  Google Scholar 

  201. Prendergast GC et al (2008) BAR the door: cancer suppression by amphiphysin-like genes. Biochim Biophys Acta. doi:10.1016/j.bbcan.2008.09.001

  202. Ryu SJ et al (2008) On the role of major vault protein in the resistance of senescent human diploid fibroblasts to apoptosis. Cell Death Differ 15(11):1673–1680. doi:10.1038/cdd.2008.96

    Article  PubMed  CAS  Google Scholar 

  203. Trost TM et al (2005) Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells. Cancer Res 65(3):840–849

    PubMed  CAS  Google Scholar 

  204. Schnabl B et al (2003) Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 37(3):653–664. doi:10.1053/jhep.2003.50097

    Article  PubMed  CAS  Google Scholar 

  205. Sebastian T et al (2005) C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. EMBO J 24(18):3301–3312. doi:10.1038/sj.emboj.7600789

    Article  PubMed  CAS  Google Scholar 

  206. Bouchard C et al (2007) FoxO transcription factors suppress Myc-driven lymphomagenesis via direct activation of Arf. Genes Dev 21(21):2775–2787. doi:10.1101/gad.453107

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work is supported by grant CA89202 from NIH to M.G.K.

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  1. Department of Pharmacology, School of Medicine, University of Pennsylvania, 1256 Biomedical Research Building II/III, 421 Curie Blvd, Philadelphia, PA, 19104-6160, USA

    M. Cecilia Caino, John Meshki & Marcelo G. Kazanietz

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  1. M. Cecilia Caino
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Caino, M.C., Meshki, J. & Kazanietz, M.G. Hallmarks for senescence in carcinogenesis: novel signaling players. Apoptosis 14, 392–408 (2009). https://doi.org/10.1007/s10495-009-0316-z

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