Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1997;75(8):1185–1194. doi: 10.1038/bjc.1997.203

Spatial association of apoptosis-related gene expression and cellular death in clinical neuroblastoma.

J C Hoehner 1, C Gestblom 1, L Olsen 1, S PÃ¥hlman 1
PMCID: PMC2222786  PMID: 9099968

Abstract

Several unique features of neuroblastoma (NB), including the capacity for spontaneous regression and maturation to benign pathology, suggest that genes that regulate cellular proliferation, survival and differentiation may be involved in directing clinical tumour aggressiveness. The in situ expression of Bcl-2, Rb, p21, p53 and Bax proteins, as well as the proliferation marker proliferating cell nuclear antigen (PCNA) were examined immunocytochemically in a selection of 38 stage- and outcome-identified NB tumours. Apoptotic cells were identified morphologically and by a DNA fragmentation labelling technique (TUNEL). Although the tumour cell density of Bcl-2, p53, Bax, PCNA and TUNEL positivity correlated with patient survival, a spatially organized expression pattern was further recognized in stroma-poor differentiating tumours. Immature tumour cells adjacent to thin fibrovascular stroma are proliferating, as evidenced by PCNA positivity, and often express Bcl-2. At increasing distance from this fibrovascular stroma, intermediately differentiated tumour cells express Rb, while with more advanced differentiation, proliferation ceases and Bcl-2 immunoreactivity is lost. The most differentiated tumour cells, which often express p53, and occasionally p21 and Bax, lie adjacent to TUNEL-positive, morphologically apoptotic cells. This spatial organization in favourable outcome NB tumours suggests that physiological regulation of differentiation and apoptosis may be involved in tumour regression.

Full text

PDF
1185

Images in this article

1188Figure 2
on p.1188

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allsopp T. E., Wyatt S., Paterson H. F., Davies A. M. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell. 1993 Apr 23;73(2):295–307. doi: 10.1016/0092-8674(93)90230-n. [DOI] [PubMed] [Google Scholar]
  2. Arends M. J., McGregor A. H., Wyllie A. H. Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras, and HPV oncogenes. Am J Pathol. 1994 May;144(5):1045–1057. [PMC free article] [PubMed] [Google Scholar]
  3. BECKWITH J. B., PERRIN E. V. IN SITU NEUROBLASTOMAS: A CONTRIBUTION TO THE NATURAL HISTORY OF NEURAL CREST TUMORS. Am J Pathol. 1963 Dec;43:1089–1104. [PMC free article] [PubMed] [Google Scholar]
  4. Beckwith J. B., Martin R. F. Observations on the histopathology of neuroblastomas. J Pediatr Surg. 1968 Feb;3(1):106–110. doi: 10.1016/0022-3468(68)90989-5. [DOI] [PubMed] [Google Scholar]
  5. Brodeur G. M. Molecular basis for heterogeneity in human neuroblastomas. Eur J Cancer. 1995;31A(4):505–510. doi: 10.1016/0959-8049(95)00040-p. [DOI] [PubMed] [Google Scholar]
  6. Brodeur G. M., Pritchard J., Berthold F., Carlsen N. L., Castel V., Castelberry R. P., De Bernardi B., Evans A. E., Favrot M., Hedborg F. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993 Aug;11(8):1466–1477. doi: 10.1200/JCO.1993.11.8.1466. [DOI] [PubMed] [Google Scholar]
  7. Buchkovich K., Duffy L. A., Harlow E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell. 1989 Sep 22;58(6):1097–1105. doi: 10.1016/0092-8674(89)90508-4. [DOI] [PubMed] [Google Scholar]
  8. Castle V. P., Heidelberger K. P., Bromberg J., Ou X., Dole M., Nuñez G. Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification. Am J Pathol. 1993 Dec;143(6):1543–1550. [PMC free article] [PubMed] [Google Scholar]
  9. Chen P. L., Scully P., Shew J. Y., Wang J. Y., Lee W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989 Sep 22;58(6):1193–1198. doi: 10.1016/0092-8674(89)90517-5. [DOI] [PubMed] [Google Scholar]
  10. Cho Y., Gorina S., Jeffrey P. D., Pavletich N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994 Jul 15;265(5170):346–355. doi: 10.1126/science.8023157. [DOI] [PubMed] [Google Scholar]
  11. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545–560. [PMC free article] [PubMed] [Google Scholar]
  12. Cordon-Cardo C., Richon V. M. Expression of the retinoblastoma protein is regulated in normal human tissues. Am J Pathol. 1994 Mar;144(3):500–510. [PMC free article] [PubMed] [Google Scholar]
  13. Cory S., Harris A. W., Strasser A. Insights from transgenic mice regarding the role of bcl-2 in normal and neoplastic lymphoid cells. Philos Trans R Soc Lond B Biol Sci. 1994 Aug 30;345(1313):289–295. doi: 10.1098/rstb.1994.0108. [DOI] [PubMed] [Google Scholar]
  14. D'Angio G. J., Evans A. E., Koop C. E. Special pattern of widespread neuroblastoma with a favourable prognosis. Lancet. 1971 May 22;1(7708):1046–1049. doi: 10.1016/s0140-6736(71)91606-0. [DOI] [PubMed] [Google Scholar]
  15. Davidoff A. M., Pence J. C., Shorter N. A., Iglehart J. D., Marks J. R. Expression of p53 in human neuroblastoma- and neuroepithelioma-derived cell lines. Oncogene. 1992 Jan;7(1):127–133. [PubMed] [Google Scholar]
  16. Dowell S. P., Hall P. A. The clinical relevance of the p53 tumour suppressor gene. Cytopathology. 1994 Jun;5(3):133–145. doi: 10.1111/j.1365-2303.1994.tb00409.x. [DOI] [PubMed] [Google Scholar]
  17. Evans A. E., Albo V., D'Angio G. J., Finklestein J. Z., Leiken S., Santulli T., Weiner J., Hammond G. D. Factors influencing survival of children with nonmetastatic neuroblastoma. Cancer. 1976 Aug;38(2):661–666. doi: 10.1002/1097-0142(197608)38:2<661::aid-cncr2820380206>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  18. Evans A. E., D'Angio G. J., Randolph J. A proposed staging for children with neuroblastoma. Children's cancer study group A. Cancer. 1971 Feb;27(2):374–378. doi: 10.1002/1097-0142(197102)27:2<374::aid-cncr2820270221>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  19. Evans A. E., Gerson J., Schnaufer L. Spontaneous regression of neuroblastoma. Natl Cancer Inst Monogr. 1976 Nov;44:49–54. [PubMed] [Google Scholar]
  20. Folkman J., Cole P., Zimmerman S. Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg. 1966 Sep;164(3):491–502. doi: 10.1097/00000658-196609000-00012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Franko A. J., Sutherland R. M. Oxygen diffusion distance and development of necrosis in multicell spheroids. Radiat Res. 1979 Sep;79(3):439–453. [PubMed] [Google Scholar]
  22. Garcia I., Martinou I., Tsujimoto Y., Martinou J. C. Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science. 1992 Oct 9;258(5080):302–304. doi: 10.1126/science.1411528. [DOI] [PubMed] [Google Scholar]
  23. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Gestblom C., Hoehner J. C., Påhlman S. Proliferation and apoptosis in neuroblastoma: subdividing the mitosis-karyorrhexis index. Eur J Cancer. 1995;31A(4):458–463. doi: 10.1016/0959-8049(95)00006-5. [DOI] [PubMed] [Google Scholar]
  25. Gimbrone M. A., Jr, Cotran R. S., Leapman S. B., Folkman J. Tumor growth and neovascularization: an experimental model using the rabbit cornea. J Natl Cancer Inst. 1974 Feb;52(2):413–427. doi: 10.1093/jnci/52.2.413. [DOI] [PubMed] [Google Scholar]
  26. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994 Sep 15;54(18):4855–4878. [PubMed] [Google Scholar]
  27. Greenlund L. J., Korsmeyer S. J., Johnson E. M., Jr Role of BCL-2 in the survival and function of developing and mature sympathetic neurons. Neuron. 1995 Sep;15(3):649–661. doi: 10.1016/0896-6273(95)90153-1. [DOI] [PubMed] [Google Scholar]
  28. Haas-Kogan D. A., Kogan S. C., Levi D., Dazin P., T'Ang A., Fung Y. K., Israel M. A. Inhibition of apoptosis by the retinoblastoma gene product. EMBO J. 1995 Feb 1;14(3):461–472. doi: 10.1002/j.1460-2075.1995.tb07022.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hall P. A., Levison D. A., Woods A. L., Yu C. C., Kellock D. B., Watkins J. A., Barnes D. M., Gillett C. E., Camplejohn R., Dover R. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol. 1990 Dec;162(4):285–294. doi: 10.1002/path.1711620403. [DOI] [PubMed] [Google Scholar]
  30. 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. 1993 Jan;8(1):203–207. [PubMed] [Google Scholar]
  31. Harper J. W., Adami G. R., Wei N., Keyomarsi K., Elledge S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805–816. doi: 10.1016/0092-8674(93)90499-g. [DOI] [PubMed] [Google Scholar]
  32. Hedborg F., Bjelfman C., Sparén P., Sandstedt B., Påhlman S. Biochemical evidence for a mature phenotype in morphologically poorly differentiated neuroblastomas with a favourable outcome. Eur J Cancer. 1995;31A(4):435–443. doi: 10.1016/0959-8049(95)00025-e. [DOI] [PubMed] [Google Scholar]
  33. Hedborg F., Ohlsson R., Sandstedt B., Grimelius L., Hoehner J. C., Pählman S. IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma. Am J Pathol. 1995 Apr;146(4):833–847. [PMC free article] [PubMed] [Google Scholar]
  34. Hockenbery D. M., Zutter M., Hickey W., Nahm M., Korsmeyer S. J. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961–6965. doi: 10.1073/pnas.88.16.6961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Hoehner J. C., Hedborg F., Wiklund H. J., Olsen L., Påhlman S. Cellular death in neuroblastoma: in situ correlation of apoptosis and bcl-2 expression. Int J Cancer. 1995 Jul 4;62(1):19–24. doi: 10.1002/ijc.2910620106. [DOI] [PubMed] [Google Scholar]
  36. Hoehner J. C., Olsen L., Sandstedt B., Kaplan D. R., Påhlman S. Association of neurotrophin receptor expression and differentiation in human neuroblastoma. Am J Pathol. 1995 Jul;147(1):102–113. [PMC free article] [PubMed] [Google Scholar]
  37. Hosoi G., Hara J., Okamura T., Osugi Y., Ishihara S., Fukuzawa M., Okada A., Okada S., Tawa A. Low frequency of the p53 gene mutations in neuroblastoma. Cancer. 1994 Jun 15;73(12):3087–3093. doi: 10.1002/1097-0142(19940615)73:12<3087::aid-cncr2820731230>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  38. Ikegaki N., Kastumata M., Tsujimoto Y. The expression and modulation of proteins associated with physiological cell death in neuroblastoma cells. Prog Clin Biol Res. 1994;385:117–122. [PubMed] [Google Scholar]
  39. Ikegaki N., Katsumata M., Tsujimoto Y., Nakagawara A., Brodeur G. M. Relationship between bcl-2 and myc gene expression in human neuroblastoma. Cancer Lett. 1995 May 8;91(2):161–168. doi: 10.1016/0304-3835(95)03746-j. [DOI] [PubMed] [Google Scholar]
  40. Ikegaki N., Temeles G., Kennett R. H. Modulation of protein expression associated with chemically induced differentiation of neuroblastoma cells. Prog Clin Biol Res. 1991;366:157–163. [PubMed] [Google Scholar]
  41. Imamura J., Bartram C. R., Berthold F., Harms D., Nakamura H., Koeffler H. P. Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification. Cancer Res. 1993 Sep 1;53(17):4053–4058. [PubMed] [Google Scholar]
  42. Jacquemier J., Molès J. P., Penault-Llorca F., Adélaide J., Torrente M., Viens P., Birnbaum D., Theillet C. p53 immunohistochemical analysis in breast cancer with four monoclonal antibodies: comparison of staining and PCR-SSCP results. Br J Cancer. 1994 May;69(5):846–852. doi: 10.1038/bjc.1994.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991 Dec 1;51(23 Pt 1):6304–6311. [PubMed] [Google Scholar]
  44. Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Krajewski S., Chatten J., Hanada M., Reed J. C. Immunohistochemical analysis of the Bcl-2 oncoprotein in human neuroblastomas. Comparisons with tumor cell differentiation and N-Myc protein. Lab Invest. 1995 Jan;72(1):42–54. [PubMed] [Google Scholar]
  46. Krajewski S., Krajewska M., Shabaik A., Miyashita T., Wang H. G., Reed J. C. Immunohistochemical determination of in vivo distribution of Bax, a dominant inhibitor of Bcl-2. Am J Pathol. 1994 Dec;145(6):1323–1336. [PMC free article] [PubMed] [Google Scholar]
  47. Kurki P., Ogata K., Tan E. M. Monoclonal antibodies to proliferating cell nuclear antigen (PCNA)/cyclin as probes for proliferating cells by immunofluorescence microscopy and flow cytometry. J Immunol Methods. 1988 Apr 22;109(1):49–59. doi: 10.1016/0022-1759(88)90441-3. [DOI] [PubMed] [Google Scholar]
  48. Lane D. P. Cancer. A death in the life of p53. Nature. 1993 Apr 29;362(6423):786–787. doi: 10.1038/362786a0. [DOI] [PubMed] [Google Scholar]
  49. Lane D. P. The regulation of p53 function: Steiner Award Lecture. Int J Cancer. 1994 Jun 1;57(5):623–627. doi: 10.1002/ijc.2910570502. [DOI] [PubMed] [Google Scholar]
  50. LeBrun D. P., Warnke R. A., Cleary M. L. Expression of bcl-2 in fetal tissues suggests a role in morphogenesis. Am J Pathol. 1993 Mar;142(3):743–753. [PMC free article] [PubMed] [Google Scholar]
  51. Lu Q. L., Poulsom R., Wong L., Hanby A. M. Bcl-2 expression in adult and embryonic non-haematopoietic tissues. J Pathol. 1993 Apr;169(4):431–437. doi: 10.1002/path.1711690408. [DOI] [PubMed] [Google Scholar]
  52. Lu X., Lane D. P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell. 1993 Nov 19;75(4):765–778. doi: 10.1016/0092-8674(93)90496-d. [DOI] [PubMed] [Google Scholar]
  53. Maltzman W., Czyzyk L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol. 1984 Sep;4(9):1689–1694. doi: 10.1128/mcb.4.9.1689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Miyashita T., Krajewski S., Krajewska M., Wang H. G., Lin H. K., Liebermann D. A., Hoffman B., Reed J. C. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene. 1994 Jun;9(6):1799–1805. [PubMed] [Google Scholar]
  55. Moll U. M., LaQuaglia M., Bénard J., Riou G. Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4407–4411. doi: 10.1073/pnas.92.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Nitschke R., Smith E. I., Shochat S., Altshuler G., Travers H., Shuster J. J., Hayes F. A., Patterson R., McWilliams N. Localized neuroblastoma treated by surgery: a Pediatric Oncology Group Study. J Clin Oncol. 1988 Aug;6(8):1271–1279. doi: 10.1200/JCO.1988.6.8.1271. [DOI] [PubMed] [Google Scholar]
  57. Nylander K., Stenling R., Gustafsson H., Zackrisson B., Roos G. p53 expression and cell proliferation in squamous cell carcinomas of the head and neck. Cancer. 1995 Jan 1;75(1):87–93. doi: 10.1002/1097-0142(19950101)75:1<87::aid-cncr2820750115>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  58. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  59. Pezzella F., Tse A. G., Cordell J. L., Pulford K. A., Gatter K. C., Mason D. Y. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed] [Google Scholar]
  60. Ramani P., Lu Q. L. Expression of bcl-2 gene product in neuroblastoma. J Pathol. 1994 Mar;172(3):273–278. doi: 10.1002/path.1711720308. [DOI] [PubMed] [Google Scholar]
  61. Rao L., Debbas M., Sabbatini P., Hockenbery D., Korsmeyer S., White E. The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7742–7746. doi: 10.1073/pnas.89.16.7742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Reed J. C. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. doi: 10.1083/jcb.124.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Rohrer H., Acheson A. L., Thibault J., Thoenen H. Developmental potential of quail dorsal root ganglion cells analyzed in vitro and in vivo. J Neurosci. 1986 Sep;6(9):2616–2624. doi: 10.1523/JNEUROSCI.06-09-02616.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Selvakumaran M., Lin H. K., Miyashita T., Wang H. G., Krajewski S., Reed J. C., Hoffman B., Liebermann D. Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways. Oncogene. 1994 Jun;9(6):1791–1798. [PubMed] [Google Scholar]
  65. Shaw P., Bovey R., Tardy S., Sahli R., Sordat B., Costa J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4495–4499. doi: 10.1073/pnas.89.10.4495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Shimada H., Chatten J., Newton W. A., Jr, Sachs N., Hamoudi A. B., Chiba T., Marsden H. B., Misugi K. Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst. 1984 Aug;73(2):405–416. doi: 10.1093/jnci/73.2.405. [DOI] [PubMed] [Google Scholar]
  67. Tannock I. F. Population kinetics of carcinoma cells, capillary endothelial cells, and fibroblasts in a transplanted mouse mammary tumor. Cancer Res. 1970 Oct;30(10):2470–2476. [PubMed] [Google Scholar]
  68. Tannock I. F. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer. 1968 Jun;22(2):258–273. doi: 10.1038/bjc.1968.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Thompson W. D., Shiach K. J., Fraser R. A., McIntosh L. C., Simpson J. G. Tumours acquire their vasculature by vessel incorporation, not vessel ingrowth. J Pathol. 1987 Apr;151(4):323–332. doi: 10.1002/path.1711510413. [DOI] [PubMed] [Google Scholar]
  70. Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
  71. Vogan K., Bernstein M., Leclerc J. M., Brisson L., Brossard J., Brodeur G. M., Pelletier J., Gros P. Absence of p53 gene mutations in primary neuroblastomas. Cancer Res. 1993 Nov 1;53(21):5269–5273. [PubMed] [Google Scholar]
  72. Vojtesek B., Lane D. P. Regulation of p53 protein expression in human breast cancer cell lines. J Cell Sci. 1993 Jul;105(Pt 3):607–612. doi: 10.1242/jcs.105.3.607. [DOI] [PubMed] [Google Scholar]
  73. White A. E., Livanos E. M., Tlsty T. D. Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev. 1994 Mar 15;8(6):666–677. doi: 10.1101/gad.8.6.666. [DOI] [PubMed] [Google Scholar]
  74. White E. Tumour biology. p53, guardian of Rb. Nature. 1994 Sep 1;371(6492):21–22. doi: 10.1038/371021a0. [DOI] [PubMed] [Google Scholar]
  75. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]
  76. Yonish-Rouach E., Resnitzky D., Lotem J., Sachs L., Kimchi A., Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature. 1991 Jul 25;352(6333):345–347. doi: 10.1038/352345a0. [DOI] [PubMed] [Google Scholar]
  77. Zambetti G. P., Bargonetti J., Walker K., Prives C., Levine A. J. Wild-type p53 mediates positive regulation of gene expression through a specific DNA sequence element. Genes Dev. 1992 Jul;6(7):1143–1152. doi: 10.1101/gad.6.7.1143. [DOI] [PubMed] [Google Scholar]
  78. el-Deiry W. S., Tokino T., Velculescu V. E., Levy D. B., Parsons R., Trent J. M., Lin D., Mercer W. E., Kinzler K. W., Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817–825. doi: 10.1016/0092-8674(93)90500-p. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES