Radiotherapy & Oncology
Volume 94, Issue 1 , Pages 90-101 , January 2010

A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis

  • Ingela Turesson

      Affiliations

    • Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden
    • Corresponding Author InformationCorresponding author. Address: Section of Oncology, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.
    • ,
  • Jan Nyman

      Affiliations

    • Department of Oncologyand
    • ,
  • Fredrik Qvarnström

      Affiliations

    • Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden
    • ,
  • Martin Simonsson

      Affiliations

    • Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden
    • ,
  • Majlis Book

      Affiliations

    • Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden
    • ,
  • Ingegerd Hermansson

      Affiliations

    • Department of Oncologyand
    • ,
  • Sunna Sigurdardottir

      Affiliations

    • Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Sweden
    • ,
  • Karl-Axel Johansson

      Affiliations

    • Department of Radiophysics, Göteborg University, Sweden

Received 15 July 2009 ,Revised 5 October 2009 ,Accepted 14 October 2009.

References 

  1. Joiner MC, Denekamp J, Maughan RL. The use of ‘top-up’ experiments to investigate the effect of very small doses per fraction in mouse skin. Int J Radiat Biol Relat Stud Phys Chem Med. 1986;49:565–580
  2. Joiner MC, Johns H. Renal damage in the mouse: the response to very small doses per fraction. Radiat Res. 1988;114:385–398
  3. Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys. 2001;49:379–389
  4. Simonsson M, Qvarnstrom F, Nyman J, Johansson KA, Garmo H, Turesson I. Low-dose hypersensitive γH2AX response and infrequent apoptosis in epidermis from radiotherapy patients. Radiother Oncol. 2008;88:388–397
  5. Marples B, Joiner MC. The elimination of low-dose hypersensitivity in Chinese hamster V79-379A cells by pretreatment with X rays or hydrogen peroxide. Radiat Res. 1995;141:160–169
  6. Enns L, Bogen KT, Wizniak J, Murtha AD, Weinfeld M. Low-dose radiation hypersensitivity is associated with p53-dependent apoptosis. Mol Cancer Res. 2004;2:557–566
  7. Krueger SA, Joiner MC, Weinfeld M, Piasentin E, Marples B. Role of apoptosis in low-dose hyper-radiosensitivity. Radiat Res. 2007;167:260–267
  8. Turesson I, Bernefors R, Book M, Flogegard M, Hermansson I, Johansson KA, et al. Normal tissue response to low doses of radiotherapy assessed by molecular markers – a study of skin in patients treated for prostate cancer. Acta Oncol. 2001;40:941–951
  9. Kaur P. Interfollicular epidermal stem cells: identification, challenges, potential. J Invest Dermatol. 2006;126:1450–1458
  10. Li A, Simmons PJ, Kaur P. Identification and isolation of candidate human keratinocyte stem cells based on cell surface phenotype. Proc Natl Acad Sci USA. 1998;95:3902–3907
  11. Potten CS, Booth C. Keratinocyte stem cells: a commentary. J Invest Dermatol. 2002;119:888–899
  12. Rachidi W, Harfourche G, Lemaitre G, Amiot F, Vaigot P, Martin MT. Sensing radiosensitivity of human epidermal stem cells. Radiother Oncol. 2007;83:267–276
  13. Watt FM, Lo Celso C, Silva-Vargas V. Epidermal stem cells: an update. Curr Opin Genet Dev. 2006;16:518–524
  14. Webb A, Li A, Kaur P. Location and phenotype of human adult keratinocyte stem cells of the skin. Differentiation. 2004;72:387–395
  15. Elkind M, Whitmore G. The radiobiology of cultured mammalian cells. New York: Gordon and Breach, New York; 1967;
  16. Sinclair WK, Morton RA. X-ray and ultraviolet sensitivity of synchronized Chinese hamster cells at various stages of the cell cycle. Biophys J. 1965;5:1–25
  17. Barendsen GW, Van Bree C, Franken NA. Importance of cell proliferative state and potentially lethal damage repair on radiation effectiveness: implications for combined tumor treatments (review). Int J Oncol. 2001;19:247–256
  18. Dikomey E. Induction and repair of DNA strand breaks in X-irradiated proliferating and quiescent CHO cells. Int J Radiat Biol. 1990;57:1169–1182
  19. Clarke AR, Gledhill S, Hooper ML, Bird CC, Wyllie AH. P53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. Oncogene. 1994;9:1767–1773
  20. Elledge SJ. Cell cycle checkpoints: preventing an identity crisis. Science. 1996;274:1664–1672
  21. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science. 1989;246:629–634
  22. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432:316–323
  23. Little JB. Delayed initiation of DNA synthesis in irradiated human diploid cells. Nature. 1968;218:1064–1065
  24. Tubiana MLH. Gray medal lecture: cell kinetics and radiation oncology. Int J Radiat Oncol Biol Phys. 1982;8:1471–1489
  25. Ren S, Rollins BJ. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell. 2004;117:239–251
  26. Sanchez I, Dynlacht BD. New insights into cyclins, CDKs, and cell cycle control. Semin Cell Dev Biol. 2005;16:311–321
  27. Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13:1501–1512
  28. Nakanishi M, Adami GR, Robetorye RS, Noda A, Venable SF, Dimitrov D, et al. Exit from G0 and entry into the cell cycle of cells expressing p21Sdi1 antisense RNA. Proc Natl Acad Sci USA. 1995;92:4352–4356
  29. Harper JW, Elledge SJ, Keyomarsi K, Dynlacht B, Tsai LH, Zhang P, et al. Inhibition of cyclin-dependent kinases by p21. Mol Biol Cell. 1995;6:387–400
  30. Weinberg WC, Denning MF. P21Waf1 control of epithelial cell cycle and cell fate. Crit Rev Oral Biol Med. 2002;13:453–464
  31. Kastan MB. DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture. Mol Cancer Res. 2008;6:517–524
  32. Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003;421:499–506
  33. Painter RB, Young BR. Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci USA. 1980;77:7315–7317
  34. Marples B, Wouters BG, Collis SJ, Chalmers AJ, Joiner MC. Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells. Radiat Res. 2004;161:247–255
  35. Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L, et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science. 1998;281:1674–1677
  36. Brugarolas J, Chandreasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 1995;377:552–557
  37. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science. 1998;281:1677–1679
  38. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–825
  39. Crook T, Marston NJ, Sara EA, Vousden KH. Transcriptional activation by p53 correlates with suppression of growth but not transformation. Cell. 1994;79:817–827
  40. Deng C, Zhang P, Harper JW, Elledge SJ, Leder P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell. 1995;82:675–684
  41. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310
  42. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993;75:805–816
  43. Bunz F, Dutriaux A, Lengauer C, Waldman T, Zhou S, Brown JP, et al. Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science. 1998;282:1497–1501
  44. Gillis LD, Leidal AM, Hill R, Lee PW. P21Cip1/WAF1 mediates cyclin B1 degradation in response to DNA damage. Cell Cycle. 2009;8:253–256
  45. Lee J, Kim JA, Barbier V, Fotedar A, Fotedar R. DNA damage triggers p21WAF1-dependent Emi1 down-regulation that maintains G2 arrest. Mol Biol Cell. 2009;20:1891–1902
  46. Moldovan GL, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007;129:665–679
  47. Sohn D, Essmann F, Schulze-Osthoff K, Janicke RU. P21 blocks irradiation-induced apoptosis downstream of mitochondria by inhibition of cyclin-dependent kinase-mediated caspase-9 activation. Cancer Res. 2006;66:11254–11262
  48. Baptiste-Okoh N, Barsotti AM, Prives C. Caspase 2 is both required for p53-mediated apoptosis and downregulated by p53 in a p21-dependent manner. Cell Cycle. 2008;7:1133–1138
  49. Janicke RU, Sohn D, Essmann F, Schulze-Osthoff K. The multiple battles fought by anti-apoptotic p21. Cell Cycle. 2007;6:407–413
  50. Wendt J, Radetzki S, von Haefen C, Hemmati PG, Guner D, Schulze-Osthoff K, et al. Induction of p21CIP/WAF-1 and G2 arrest by ionizing irradiation impedes caspase-3-mediated apoptosis in human carcinoma cells. Oncogene. 2006;25:972–980
  51. Kuribayashi K, El-Deiry WS. Regulation of programmed cell death by the p53 pathway. Adv Exp Med Biol. 2008;615:201–221
  52. Coates PJ, Lorimore SA, Lindsay KJ, Wright EG. Tissue-specific p53 responses to ionizing radiation and their genetic modification: the key to tissue-specific tumour susceptibility?. J Pathol. 2003;201:377–388
  53. Fei P, Bernhard EJ, El-Deiry WS. Tissue-specific induction of p53 targets in vivo. Cancer Res. 2002;62:7316–7327
  54. Gudkov AV, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer. 2003;3:117–129
  55. Garner E, Raj K. Protective mechanisms of p53-p21-pRb proteins against DNA damage-induced cell death. Cell Cycle. 2008;7:277–282
  56. Stoyanova T, Roy N, Kopanja D, Bagchi S, Raychaudhuri P. DDB2 decides cell fate following DNA damage. Proc Natl Acad Sci USA. 2009;106:10690–10695
  57. Paris R, Henry RE, Stephens SJ, McBryde M, Espinosa JM. Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation. Cell Cycle. 2008;7:2427–2433
  58. Tang X, Hui ZG, Cui XL, Garg R, Kastan MB, Xu B. A novel ATM-dependent pathway regulates protein phosphatase 1 in response to DNA damage. Mol Cell Biol. 2008;28:2559–2566
  59. Xu B, Kim ST, Lim DS, Kastan MB. Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation. Mol Cell Biol. 2002;22:1049–1059
  60. Short SC, Woodcock M, Marples B, Joiner MC. Effects of cell cycle phase on low-dose hyper-radiosensitivity. Int J Radiat Biol. 2003;79:99–105
  61. Hirata A, Inada K, Tsukamoto T, Sakai H, Mizoshita T, Yanai T, et al. Characterization of a monoclonal antibody, HTA28, recognizing a histone H3 phosphorylation site as a useful marker of M-phase cells. J Histochem Cytochem. 2004;52:1503–1509
  62. Bae I, Fan S, Bhatia K, Kohn KW, Fornace AJ, O’Connor PM. Relationships between G1 arrest and stability of the p53 and p21Cip1/Waf1 proteins following gamma-irradiation of human lymphoma cells. Cancer Res. 1995;55:2387–2393
  63. Blagosklonny MV, Wu GS, Omura S, el-Deiry WS. Proteasome-dependent regulation of p21WAF1/CIP1 expression. Biochem Biophys Res Commun. 1996;227:564–569
  64. Bloom J, Amador V, Bartolini F, DeMartino G, Pagano M. Proteasome-mediated degradation of p21 via N-terminal ubiquitinylation. Cell. 2003;115:71–82
  65. Daino K, Ichimura S, Nenoi M. Early induction of CDKN1A (p21) and GADD45 mRNA by a low dose of ionizing radiation is due to their dose-dependent post-transcriptional regulation. Radiat Res. 2002;157:478–482
  66. Jin Y, Lee H, Zeng SX, Dai MS, Lu H. MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation. EMBO J. 2003;22:6365–6377
  67. Kim MJ, Lee JY, Lee SJ. Transient suppression of nuclear Cdc2 activity in response to ionizing radiation. Oncol Rep. 2008;19:1323–1329
  68. Mirzayans R, Scott A, Cameron M, Murray D. Induction of accelerated senescence by gamma radiation in human solid tumor-derived cell lines expressing wild-type TP53. Radiat Res. 2005;163:53–62
  69. Sheaff RJ, Singer JD, Swanger J, Smitherman M, Roberts JM, Clurman BE. Proteasomal turnover of p21Cip1 does not require p21Cip1 ubiquitination. Mol Cell. 2000;5:403–410
  70. Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7:1126–1132
  71. Amundson SA, Bittner M, Fornace AJ. Functional genomics as a window on radiation stress signaling. Oncogene. 2003;22:5828–5833
  72. Bernhard EJ, McKenna WG, Muschel RJ. Cyclin expression and G2-phase delay after irradiation. Radiat Res. 1994;138:S64–S67
  73. Maity A, McKenna WG, Muschel RJ. The molecular basis for cell cycle delays following ionizing radiation: a review. Radiother Oncol. 1994;31:1–13
  74. Artuso M, Esteve A, Bresil H, Vuillaume M, Hall J. The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1(p21)- and GADD45-mediated response to DNA damage produced by ionising radiation. Oncogene. 1995;11:1427–1435
  75. Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y, et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature. 2000;406:210–215
  76. Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H, et al. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature. 1997;389:187–190
  77. Xu B, Kim S, Kastan MB. Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation. Mol Cell Biol. 2001;21:3445–3450
  78. Wouters BG, Denko NC, Giaccia AJ, Brown JM. A p53 and apoptotic independent role for p21waf1 in tumour response to radiation therapy. Oncogene. 1999;18:6540–6545
  79. Abbas T, Dutta A. P21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–414
  80. DeSimone JN, Bengtsson U, Wang X, Lao XY, Redpath JL, Stanbridge EJ. Complexity of the mechanisms of initiation and maintenance of DNA damage-induced G2-phase arrest and subsequent G1-phase arrest: TP53-dependent and TP53-independent roles. Radiat Res. 2003;159:72–85
  81. Toettcher JE, Loewer A, Ostheimer GJ, Yaffe MB, Tidor B, Lahav G. Distinct mechanisms act in concert to mediate cell cycle arrest. Proc Natl Acad Sci USA. 2009;106:785–790
  82. Bartek J, Lukas J. DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol. 2007;19:238–245
  83. Lobrich M, Jeggo PA. The impact of a negligent G2/M checkpoint on genomic instability and cancer induction. Nat Rev Cancer. 2007;7:861–869
  84. Chu K, Teele N, Dewey MW, Albright N, Dewey WC. Computerized video time lapse study of cell cycle delay and arrest, mitotic catastrophe, apoptosis and clonogenic survival in irradiated 14-3-3sigma and CDKN1A (p21) knockout cell lines. Radiat Res. 2004;162:270–286
  85. von Wangenheim KH, Peterson HP, Schwenke K. Review: a major component of radiation action: interference with intracellular control of differentiation. Int J Radiat Biol. 1995;68:369–388
  86. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. 2009;137:413–431
  87. Harney J, Short SC, Shah N, Joiner M, Saunders MI. Low dose hyper-radiosensitivity in metastatic tumors. Int J Radiat Oncol Biol Phys. 2004;59:1190–1195
  88. Honore HB, Bentzen SM. A modelling study of the potential influence of low dose hypersensitivity on radiation treatment planning. Radiother Oncol. 2006;79:115–121
  89. Lin PS, Wu A. Not all 2 Gray radiation prescriptions are equivalent: cytotoxic effect depends on delivery sequences of partial fractionated doses. Int J Radiat Oncol Biol Phys. 2005;63:536–544

PII: S0167-8140(09)00587-8

doi: 10.1016/j.radonc.2009.10.007

Radiotherapy & Oncology
Volume 94, Issue 1 , Pages 90-101 , January 2010

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