The role of p53 in determining sensitivity to radiotherapy (original) (raw)

• Santana, P. et al. Acid sphingomyelinase-deficient human lymphoblasts and mice are defective in radiation-induced apoptosis. Cell 86, 189–199 (1996).
  CAS PubMed Google Scholar
• Fowler, J. F. Biological factors influencing optimum fractionation in radiation therapy. Acta Oncol. 40, 712–717 (2001).
  CAS PubMed Google Scholar
• Wahl, G. M. & Carr, A. M. The evolution of diverse biological responses to DNA damage: insights from yeast and p53. Nature Cell Biol. 3, E277–E286 (2001).
  CAS PubMed Google Scholar
• Lowndes, N. F. & Murguia, J. R. Sensing and responding to DNA damage. Curr. Opin. Genet. Dev. 10, 17–25 (2000).
  CAS PubMed Google Scholar
• Neta, R., Oppenheim, J. J. & Douches, S. D. Interdependence of the radioprotective effects of human recombinant interleukin 1 alpha, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-stimulating factor. J. Immunol. 140, 108–111 (1988).
  CAS PubMed Google Scholar
• Kemp, C. J., Sun, S. & Gurley, K. E. p53 induction and apoptosis in response to radio- and chemotherapy in vivo is tumor-type-dependent. Cancer Res. 61, 327–332 (2001). Shows that the experimental mouse tumours that respond to cancer treatment by apoptosis originate from apoptosis-prone tissues.
  CAS PubMed Google Scholar
• Smith, M. L. p53 regulation of DNA excision repair pathways. Mutagenesis 17, 149–156 (2002).
  CAS PubMed Google Scholar
• Dasika, G. K. et al. DNA damage-induced cell cycle checkpoints and DNA strand break repair in development and tumorigenesis. Oncogene 18, 7883–7899 (1999).
  CAS PubMed Google Scholar
• Lowe, S. W. & Lin, A. W. Apoptosis in cancer. Carcinogenesis 21, 485–495 (2000).
  CAS PubMed Google Scholar
• Ko, L. J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054–1072 (1996).
  CAS PubMed Google Scholar
• el-Deiry, W. S. Regulation of p53 downstream genes. Semin. Cancer Biol. 8, 345–357 (1998).
  CAS PubMed Google Scholar
• Offer, H. et al. The onset of p53-dependent DNA repair or apoptosis is determined by the level of accumulated damaged DNA. Carcinogenesis 23, 1025–1032 (2002).
  CAS PubMed Google Scholar
• Vousden, K. H. p53: death star. Cell 103, 691–694 (2000).
  CAS PubMed Google Scholar
• Schmitt, C. A., Rosenthal, C. T. & Lowe, S. W. Genetic analysis of chemoresistance in primary murine lymphomas. Nature Med. 6, 1029–1035 (2000).
  CAS PubMed Google Scholar
• Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001).
  CAS PubMed Google Scholar
• Oda, K. et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000).
  CAS PubMed Google Scholar
• Khanna, K. K. et al. Cellular Responses to DNA Damage and the Human Chromosome Instability Syndromes (Humana Press, San Diego, 1998).
  Google Scholar
• Shiloh, Y. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31, 635–662 (1997).
  CAS PubMed Google Scholar
• Woods, C. G. DNA repair disorders. Arch. Dis. Child. 78, 178–184 (1998).
  CAS PubMed PubMed Central Google Scholar
• Auerbach, A. D. & Verlander, P. C. Disorders of DNA replication and repair. Curr. Opin. Pediatr. 9, 600–616 (1997).
  CAS PubMed Google Scholar
• Denekamp, J. Cell kinetics and radiation biology. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 49, 357–380 (1986).
  CAS PubMed Google Scholar
• Sinclair, W. K. in Time and Dose Relationships in Radiation Biology as Applied to Radiotherapy. BNL Reports 50203 (C-57), 97–107 (1969).
  Google Scholar
• Sinclair, W. K. _N_-ethylmaleimide and the cyclic response to X-rays of synchronous Chinese hamster cells. Radiat. Res. 55, 41–57 (1973).
  CAS PubMed Google Scholar
• Komarova, E. A. et al. Stress-induced secretion of growth inhibitors: a novel tumor suppressor function of p53. Oncogene 17, 1089–1096 (1998).
  CAS PubMed Google Scholar
• Takai, H. et al. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21, 5195–5205 (2002).
  CAS PubMed PubMed Central Google Scholar
• Bunz, F. et al. Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J. Clin. Invest. 104, 263–269 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Hawkins, D. S., Demers, G. W. & Galloway, D. A. Inactivation of p53 enhances sensitivity to multiple chemotherapeutic agents. Cancer Res. 56, 892–898 (1996). Inactivation of p53 might cause cell sensitization to treatment with anticancer agents.
  CAS PubMed Google Scholar
• Palacios, C., Gutierrez del Arroyo, A., Silva, A. & Collins, M. K. The role of p53 in death of IL-3-dependent cells in response to cytotoxic drugs. Oncogene 19, 3556–3559 (2000).
  CAS PubMed Google Scholar
• Offer, H. et al. p53 modulates base excision repair activity in a cell cycle-specific manner after genotoxic stress. Cancer Res. 61, 88–96 (2001).
  CAS PubMed Google Scholar
• Pardo, F. S. et al. Transfection of rat embryo cells with mutant p53 increases the intrinsic radiation resistance. Radiat. Res. 140, 180–185 (1994).
  CAS PubMed Google Scholar
• Wang, L. et al. Gamma-ray-induced cell killing and chromosome abnormalities in the bone marrow of p53-deficient mice. Radiat. Res. 146, 259–266 (1996).
  CAS PubMed Google Scholar
• DiBiase, S. J., Guan, J., Curran, W. J., Jr & Iliakis, G. Repair of DNA double-strand breaks and radiosensitivity to killing in an isogenic group of p53 mutant cell lines. Int. J. Radiat. Oncol. Biol. Phys. 45, 743–751 (1999).
  CAS PubMed Google Scholar
• Gudkov, A. V. Converting p53 from a killer into a healer. Nature Med. 8, 1196–1198 (2002).
  CAS PubMed Google Scholar
• Seo, Y. R., Kelley, M. & Smith, M. L. Selenomethionine regulation of p53 by a ref-1-dependent redox mechanism. Proc. Natl Acad. Sci. USA 99, 13969–13971 (2002).
  Google Scholar
• Schultheiss, T. E., Kun, L. E., Ang, K. K. & Stephens, L. C. Radiation response of the central nervous system. Int. J. Radiat. Oncol. Biol. Phys. 31, 1093–1112 (1995).
  CAS PubMed Google Scholar
• Michel, C. Radiation embryology. Experientia 45, 69–77 (1989).
  CAS PubMed Google Scholar
• Chang, B. D. et al. A senescence-like phenotype distinguishes tumor cells that undergo terminal proliferation arrest after exposure to anticancer agents. Cancer Res. 59, 3761–3767 (1999).
  CAS PubMed Google Scholar
• Chang, B. D. et al. p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene 19, 2165–2170 (2000).
  CAS PubMed Google Scholar
• Macip, S. et al. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J. 21, 2180–2188 (2002). References 37–39 show that senescence-like permanent growth arrest can be an important type of tumour-cell response to treatment with DNA-damaging agents.
  CAS PubMed PubMed Central Google Scholar
• Wang, J. Y., Naderi, S. & Chen, T. T. Role of retinoblastoma tumor suppressor protein in DNA damage response. Acta Oncol. 40, 689–695 (2001). The role of RB is essential for the establishment of irreversible growth arrest in response to IR: inactivation of RB allows the cell to resume proliferation after prolonged p53-dependent growth arrest following severe DNA damage.
  CAS PubMed Google Scholar
• Song, S. & Lambert, P. F. Different responses of epidermal and hair follicular cells to radiation correlate with distinct patterns of p53 and p21 induction. Am. J. Pathol. 155, 1121–1127 (1999).
  CAS PubMed PubMed Central Google Scholar
• Komarova, E. A. et al. Transgenic mice with p53-responsive lacZ: p53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo. EMBO J. 16, 1391–1400 (1997).
  CAS PubMed PubMed Central Google Scholar
• Komarova, E. A., Christov, K., Faerman, A. I. & Gudkov, A. V. Different impact of p53 and p21 on the radiation response of mouse tissues. Oncogene 19, 3791–3798 (2000).
  CAS PubMed Google Scholar
• Lowe, S. W., Schmitt, E. M., Smith, S. W., Osborne, B. A. & Jacks, T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362, 847–849 (1993).
  CAS PubMed Google Scholar
• MacCallum, D. E. et al. The p53 response to ionising radiation in adult and developing murine tissues. Oncogene 13, 2575–2587 (1996).
  CAS PubMed Google Scholar
• Westphal, C. H. et al. Atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nature Genet. 16, 397–401 (1997). References 41–46 illustrate the role of p53-dependent apoptosis in normal tissue damage by IR, indicating that p53 might be a determinant of the side effects of cancer treatment.
  CAS PubMed Google Scholar
• Komarov, P. G. et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 285, 1733–1737 (1999). Identification (by chemical library screening) and in vivo and in vitro testing of a p53 inhibitor as an approach to reduce IR-induced tissue damage.
  CAS PubMed Google Scholar
• Hall, P. A., McKee, P. H., Menage, H. D., Dover, R. & Lane, D. P. High levels of p53 protein in UV-irradiated normal human skin. Oncogene 8, 203–207 (1993).
  CAS PubMed Google Scholar
• Campbell, C., Quinn, A. G., Angus, B., Farr, P. M. & Rees, J. L. Wavelength specific patterns of p53 induction in human skin following exposure to UV radiation. Cancer Res. 53, 2697–2699 (1993).
  CAS PubMed Google Scholar
• Merritt, A. J. et al. The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. Cancer Res. 54, 614–617 (1994).
  CAS PubMed Google Scholar
• Clarke, A. R., Gledhill, S., Hooper, M. L., Bird, C. C. & Wyllie, A. H. p53 dependence of early apoptotic and proliferative responses within the mouse intestinal epithelium following gamma-irradiation. Oncogene 9, 1767–1773 (1994). References 50 and 51 describe the p53 dependence of IR-induced damage to the epithelium of the small intestine.
  CAS PubMed Google Scholar
• Midgley, C. A. et al. Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo. J. Cell Sci. 108, 1843–1848 (1995).
  CAS PubMed Google Scholar
• Rogel, A., Popliker, M., Webb, C. G. & Oren, M. p53 cellular tumor antigen: analysis of mRNA levels in normal adult tissues, embryos, and tumors. Mol. Cell. Biol. 5, 2851–2855 (1985).
  CAS PubMed PubMed Central Google Scholar
• Burns, T. F., Bernhard, E. J. & El-Deiry, W. S. Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo. Oncogene 20, 4601–4612 (2001).
  CAS PubMed Google Scholar
• Haks, M. C., Krimpenfort, P., van den Brakel, J. H. & Kruisbeek, A. M. Pre-TCR signaling and inactivation of p53 induces crucial cell survival pathways in pre-T cells. Immunity 11, 91–101 (1999).
  CAS PubMed Google Scholar
• Guidos, C. J. et al. V(D)J recombination activates a p53-dependent DNA damage checkpoint in SCID lymphocyte precursors. Genes Dev. 10, 2038–2054 (1996).
  CAS PubMed Google Scholar
• Newmeyer, D. D. & Green, D. R. Surviving the cytochrome seas. Neuron 21, 653–655 (1998).
  CAS PubMed Google Scholar
• Li, F. et al. Cell-specific induction of apoptosis by microinjection of cytochrome c. Bcl-xL has activity independent of cytochrome c release. J. Biol. Chem. 272, 30299–30305 (1997).
  CAS PubMed Google Scholar
• Deshmukh, M. & Johnson, E. M. Jr. Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21, 695–705 (1998).
  CAS PubMed Google Scholar
• Westphal, C. H. et al. Loss of Atm radiosensitizes multiple p53 null tissues. Cancer Res. 58, 5637–5639 (1998).
  CAS PubMed Google Scholar
• Paris, F. et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 293, 293–297 (2001). Tissue failure in response to IR can result from the selective damage of the most sensitive tissue component (in this case, the endothelium), leading to a chain reaction of pathological consequences.
  CAS PubMed Google Scholar
• Chow, B. M., Li, Y. Q. & Wong, C. S. Radiation-induced apoptosis in the adult central nervous system is p53- dependent. Cell Death Differ. 7, 712–720 (2000).
  CAS PubMed Google Scholar
• Weichselbaum, R. R., Epstein, J. & Little, J. B. In vitro radiosensitivity of human dipliod fibroblasts derived from patients with unusual clinical responses to radiation. Radiology 121, 479–482 (1976).
  CAS PubMed Google Scholar
• Barcellos-Hoff, M. H. Radiation-induced transforming growth factor beta and subsequent extracellular matrix reorganization in murine mammary gland. Cancer Res. 53, 3880–3886 (1993).
  CAS PubMed Google Scholar
• Flanders, K. C. et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am. J. Pathol. 160, 1057–1068 (2002).
  CAS PubMed PubMed Central Google Scholar
• Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).
  CAS PubMed Google Scholar
• Schmitt, C. A. & Lowe, S. W. Bcl-2 mediates chemoresistance in matched pairs of primary E(mu)-myc lymphomas in vivo. Blood Cells Mol. Dis. 27, 206–216 (2001).
  CAS PubMed Google Scholar
• Cordon-Cardo, C., Dalbagni, G., Sarkis, A. S. & Reuter, V. E. Genetic alterations associated with bladder cancer. Important Adv. Oncol. [vol?] 71–83 (1994).
• Falette, N. et al. Prognostic value of p53 gene mutations in a large series of node-negative breast cancer patients. Cancer Res. 58, 1451–1455 (1998).
  CAS PubMed Google Scholar
• Molina, R. et al. p53 oncoprotein as a prognostic indicator in patients with breast cancer. Anticancer Res. 18, 507–511 (1998).
  CAS PubMed Google Scholar
• Brown, J. M. & Wouters, B. G. Apoptosis: mediator or mode of cell killing by anticancer agents? Drug Resist. Update 4, 135–136 (2001).
  CAS Google Scholar
• Nieder, C., Petersen, S., Petersen, C. & Thames, H. D. The challenge of p53 as prognostic and predictive factor in gliomas. Cancer Treat. Rev. 26, 67–73 (2000).
  CAS PubMed Google Scholar
• Sierra, A. et al. Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: a pathway to metastatic progression in human breast cancer. Int. J. Cancer 89, 142–147 (2000).
  CAS PubMed Google Scholar
• Deveraux, Q. L. et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223 (1998).
  CAS PubMed PubMed Central Google Scholar
• Beere, H. M. et al. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nature Cell Biol. 2, 469–475 (2000).
  CAS PubMed Google Scholar
• Lowe, S. W. et al. p53 status and the efficacy of cancer therapy in vivo. Science 266, 807–810 (1994). This paper had a very strong impact in the field by establishing the concept of p53-dependent apoptosis as the mechanism of treatment sensitivity of tumours.
  CAS PubMed Google Scholar
• Malumbres, M. & Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nature Rev. Cancer 1, 222–231 (2001).
  CAS Google Scholar
• Roninson, I. B., Broude, E. V. & Chang, B. D. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist. Update 4, 303–313 (2001).
  CAS Google Scholar
• Hendry, J. H. & West, C. M. Apoptosis and mitotic cell death: their relative contributions to normal-tissue and tumour radiation response. Int. J. Radiat. Biol. 71, 709–719 (1997).
  CAS PubMed Google Scholar
• Ianzini, F. & Mackey, M. A. Delayed DNA damage associated with mitotic catastrophe following X-irradiation of HeLa S3 cells. Mutagenesis 13, 337–344 (1998).
  CAS PubMed Google Scholar
• Abend, M., Gilbertz, K. P., Rhein, A. & van Beuningen, D. Early and late G2 arrest of cells undergoing radiation-induced apoptosis or micronucleation. Cell Prolif. 29, 101–113 (1996).
  CAS PubMed Google Scholar
• Dini, L., Coppola, S., Ruzittu, M. T. & Ghibelli, L. Multiple pathways for apoptotic nuclear fragmentation. Exp. Cell Res. 223, 340–347 (1996).
  CAS PubMed Google Scholar
• Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). Blocking the apoptotic programme in tumours of immunocyte origin causes a switch to an alternative type of p53-mediated response to treatment in vivo — senescence-like permanent arrest.
  CAS PubMed Google Scholar
• Slichenmyer, W. J., Nelson, W. G., Slebos, R. J. & Kastan, M. B. Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res. 53, 4164–4168 (1993).
  CAS PubMed Google Scholar
• Brachman, D. G. et al. p53 mutation does not correlate with radiosensitivity in 24 head and neck cancer cell lines. Cancer Res. 53, 3667–3669 (1993). References 84 and 85 show that wild-type p53 in the tumour is not necessarily associated with higher sensitivity to treatment.
  CAS PubMed Google Scholar
• Graeber, T. G. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996).
  CAS PubMed Google Scholar
• Gurova, K. V. et al. Apoptosis inhibitor as a suppressor of tumor progression: expression of Bcl-2 eliminates selective advantages for p53-deficient cells in the tumor. Cancer Biol. Ther. 1, 39–44; discussion 45–46 (2002).
  CAS PubMed Google Scholar
• Gurova, K. & Gudkov, A. V. Paradoxical role of apoptosis in cancer progression. J. Cell Biochem. 88, 128–137 (2003).
  CAS PubMed Google Scholar
• Komarova, E. A. & Gudkov, A. V. Could p53 be a target for therapeutic suppression? Semin. Cancer Biol. 8, 389–400 (1998).
  CAS PubMed Google Scholar
• Funk, J. O., Samuel, T. & Weber, H. O. in Cell Cycle Checkpoints and Cancer (ed. Blagosklonny, M. V.) 64–77 (Eurekah, Austin, Texas, 2001).
  Google Scholar
• Khanna, K. K., Lavin, M. F., Jackson, S. P. & Mulhern, T. D. ATM, a central controller of cellular responses to DNA damage. Cell Death Differ. 8, 1052–1065 (2001).
  CAS PubMed Google Scholar
• Tuteja, N. & Tuteja, R. Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect. Crit. Rev. Biochem. Mol. Biol. 36, 261–290 (2001).
  CAS PubMed Google Scholar
• Rosen, E. M., Fan, S., Rockwell, S. & Goldberg, I. D. The molecular and cellular basis of radiosensitivity: implications for understanding how normal tissues and tumors respond to therapeutic radiation. Cancer Invest. 17, 56–72 (1999).
  CAS PubMed Google Scholar
• Bernstein, C., Bernstein, H., Payne, C. M. & Garewal, H. DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis. Mutat. Res. 511, 145–178 (2002).
  CAS PubMed Google Scholar
• Prives, C. & Hall, P. A. The p53 pathway. J. Pathol. 187, 112–126 (1999).
  CAS PubMed Google Scholar
• Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. Nature Rev. Cancer 2, 594–604 (2002).
  CAS Google Scholar
• Ford, J. M. & Hanawalt, P. C. Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J. Biol. Chem. 272, 28073–28080 (1997). References 34 and 97 indicate a direct involvement of p53 in DNA repair.
  CAS PubMed Google Scholar
• Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).
  CAS PubMed Google Scholar
• Schuler, M. & Green, D. R. Mechanisms of p53-dependent apoptosis. Biochem. Soc. Trans. 29, 684–688 (2001).
  CAS PubMed Google Scholar
• Li, H., Zhu, H., Xu, C. J. & Yuan, J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501 (1998).
  CAS PubMed Google Scholar
• Sheard, M. A. Ionizing radiation as a response-enhancing agent for CD95-mediated apoptosis. Int. J. Cancer 96, 213–220 (2001).
  CAS PubMed Google Scholar
• Embree-Ku, M., Venturini, D. & Boekelheide, K. Fas is involved in the p53-dependent apoptotic response to ionizing radiation in mouse testis. Biol. Reprod. 66, 1456–1461 (2002).
  CAS PubMed Google Scholar
• McGowan, C. H. Checking in on Cds1 (Chk2): a checkpoint kinase and tumor suppressor. Bioessays 24, 502–511 (2002).
  CAS PubMed Google Scholar
• Albrechtsen, N. et al. Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 18, 7706–7717 (1999).
  CAS PubMed Google Scholar
• Troelstra, C. et al. Molecular cloning of the human DNA excision repair gene ERCC-6. Mol. Cell. Biol. 10, 5806–5813 (1990).
  CAS PubMed PubMed Central Google Scholar
• Buchhop, S. et al. Interaction of p53 with the human Rad51 protein. Nucleic Acids Res. 25, 3868–3874 (1997).
  CAS PubMed PubMed Central Google Scholar
• Basu, S. & Kolesnick, R. Stress signals for apoptosis: ceramide and c-Jun kinase. Oncogene 17, 3277–3285 (1998).
  PubMed Google Scholar
• Kolesnick, R. The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J. Clin. Invest. 110, 3–8 (2002).
  CAS PubMed PubMed Central Google Scholar
• Aladjem, M. I. et al. ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage. Curr. Biol. 8, 145–155 (1998).
  CAS PubMed Google Scholar
• Norimura, T., Nomoto, S., Katsuki, M., Gondo, Y. & Kondo, S. p53-dependent apoptosis suppresses radiation-induced teratogenesis. Nature Med. 2, 577–580 (1996). Loss of p53 in mice is associated with a marked increase in the teratogenic effect of IR, presumably because genetically damaged cells are no longer eliminated by p53-mediated apoptosis. These observations allowed David Lane to name p53 “a guardian of babies”.
  CAS PubMed Google Scholar
• Brash, D. E. Cellular proofreading. Nature Med. 2, 525–526 (1996).
  CAS PubMed Google Scholar
• Hall, P. A. & Lane, D. P. Tumor suppressors: a developing role for p53? Curr. Biol. 7, R144–R147 (1997).
  CAS PubMed Google Scholar
• Vos, O. Effects and consequences of prenatal irradiation. Boll. Soc. Ital. Biol. Sper. 65, 481–500 (1989).
  CAS PubMed Google Scholar
• Hendry, J. H., Cai, W. B., Roberts, S. A. & Potten, C. S. p53 deficiency sensitizes clonogenic cells to irradiation in the large but not the small intestine. Radiat. Res. 148, 254–259 (1997).
  CAS PubMed Google Scholar
• Hasegawa, M., Zhang, Y., Niibe, H., Terry, N. H. & Meistrich, M. L. Resistance of differentiating spermatogonia to radiation-induced apoptosis and loss in p53-deficient mice. Radiat. Res. 149, 263–270 (1998).
  CAS PubMed Google Scholar
• Tron, V. A. et al. p53-regulated apoptosis is differentiation dependent in ultraviolet B- irradiated mouse keratinocytes. Am. J. Pathol. 153, 579–585 (1998).
  CAS PubMed PubMed Central Google Scholar
• Frenkel, J. et al. Accentuated apoptosis in normally developing p53 knockout mouse embryos following genotoxic stress. Oncogene 18, 2901–2907 (1999).
  CAS PubMed Google Scholar
• Uberti, D. et al. Epithelial cells of different organs exhibit distinct patterns of p53-dependent and p53-independent apoptosis following DNA insult. Exp. Cell Res. 252, 123–133 (1999).
  CAS PubMed Google Scholar
• Hendry, J. H., Adeeko, A., Potten, C. S. & Morris, I. D. p53 deficiency produces fewer regenerating spermatogenic tubules after irradiation. Int. J. Radiat. Biol. 70, 677–682 (1996).
  CAS PubMed Google Scholar
• Rojas, A. & Denekamp, J. Modifiers of radiosensitivity. Experientia 45, 41–52 (1989).
  CAS PubMed Google Scholar
• Jordan, B. F. et al. Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide-dependent decrease of the tumor cells oxygen consumption. Cancer Res. 62, 3555–3561 (2002).
  CAS PubMed Google Scholar
• Neta, R., Douches, S. & Oppenheim, J. J. Interleukin 1 is a radioprotector. J. Immunol. 136, 2483–2485 (1986).
  CAS PubMed Google Scholar
• Zsebo, K. M. et al. Radioprotection of mice by recombinant rat stem cell factor. Proc. Natl Acad. Sci. USA 89, 9464–9468 (1992).
  CAS PubMed PubMed Central Google Scholar
• Neta, R., Stiefel, S. M., Finkelman, F., Herrmann, S. & Ali, N. IL-12 protects bone marrow from and sensitizes intestinal tract to ionizing radiation. J. Immunol. 153, 4230–4237 (1994).
  CAS PubMed Google Scholar
• King, D. P. & Takahashi, J. S. Molecular genetics of circadian rhythms in mammals. Annu. Rev. Neurosci. 23, 713–742 (2000).
  CAS PubMed Google Scholar
• Haus, E. Chronobiology of the mammalian response to ionizing radiation potential applications in oncology. Chronobiol. Int. 19, 77–100 (2002).
  PubMed Google Scholar