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. 1996 Sep 2;15(17):4566–4573.

Anti-apoptotic activity of low levels of wild-type p53.

P Lassus 1, M Ferlin 1, J Piette 1, U Hibner 1
PMCID: PMC452186  PMID: 8887548

Abstract

Induction of apoptosis is a function of both an external stimulus and the physiology of the cell, which includes the expression of multiple oncogenes and tumor suppressors. Here we have studied the apoptotic response of immortalized mouse fibroblasts to serum withdrawal. We show that, in addition to the p53-independent apoptosis observed in p53- cells, overexpression of wild-type p53 tumor suppressor results in a high rate of programmed cell death. However, physiological range, low levels of the p53 protein protect fibroblasts from induction of apoptosis. Our results indicate that, as a function of its dose, the wild-type p53 can either protect from death or promote apoptosis. This new, anti-apoptotic, activity of p53 may have implications for the understanding of the role played by p53 in embryonic development as well as in initial stages of oncogenesis.

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Selected References

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  1. Bissonnette R. P., Echeverri F., Mahboubi A., Green D. R. Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature. 1992 Oct 8;359(6395):552–554. doi: 10.1038/359552a0. [DOI] [PubMed] [Google Scholar]
  2. Caelles C., Helmberg A., Karin M. p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature. 1994 Jul 21;370(6486):220–223. doi: 10.1038/370220a0. [DOI] [PubMed] [Google Scholar]
  3. Canman C. E., Gilmer T. M., Coutts S. B., Kastan M. B. Growth factor modulation of p53-mediated growth arrest versus apoptosis. Genes Dev. 1995 Mar 1;9(5):600–611. doi: 10.1101/gad.9.5.600. [DOI] [PubMed] [Google Scholar]
  4. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  5. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  6. Evan G. I., Wyllie A. H., Gilbert C. S., Littlewood T. D., Land H., Brooks M., Waters C. M., Penn L. Z., Hancock D. C. Induction of apoptosis in fibroblasts by c-myc protein. Cell. 1992 Apr 3;69(1):119–128. doi: 10.1016/0092-8674(92)90123-t. [DOI] [PubMed] [Google Scholar]
  7. Fanidi A., Harrington E. A., Evan G. I. Cooperative interaction between c-myc and bcl-2 proto-oncogenes. Nature. 1992 Oct 8;359(6395):554–556. doi: 10.1038/359554a0. [DOI] [PubMed] [Google Scholar]
  8. Fujiwara T., Grimm E. A., Mukhopadhyay T., Cai D. W., Owen-Schaub L. B., Roth J. A. A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res. 1993 Sep 15;53(18):4129–4133. [PubMed] [Google Scholar]
  9. 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]
  10. Gossen M., Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547–5551. doi: 10.1073/pnas.89.12.5547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Graeber T. G., Osmanian C., Jacks T., Housman D. E., Koch C. J., Lowe S. W., Giaccia A. J. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996 Jan 4;379(6560):88–91. doi: 10.1038/379088a0. [DOI] [PubMed] [Google Scholar]
  12. Haffner R., Oren M. Biochemical properties and biological effects of p53. Curr Opin Genet Dev. 1995 Feb;5(1):84–90. doi: 10.1016/s0959-437x(95)90058-6. [DOI] [PubMed] [Google Scholar]
  13. Harrington E. A., Bennett M. R., Fanidi A., Evan G. I. c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. EMBO J. 1994 Jul 15;13(14):3286–3295. doi: 10.1002/j.1460-2075.1994.tb06630.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Harris C. C. p53: at the crossroads of molecular carcinogenesis and risk assessment. Science. 1993 Dec 24;262(5142):1980–1981. doi: 10.1126/science.8266092. [DOI] [PubMed] [Google Scholar]
  15. Harvey D. M., Levine A. J. p53 alteration is a common event in the spontaneous immortalization of primary BALB/c murine embryo fibroblasts. Genes Dev. 1991 Dec;5(12B):2375–2385. doi: 10.1101/gad.5.12b.2375. [DOI] [PubMed] [Google Scholar]
  16. Hermeking H., Eick D. Mediation of c-Myc-induced apoptosis by p53. Science. 1994 Sep 30;265(5181):2091–2093. doi: 10.1126/science.8091232. [DOI] [PubMed] [Google Scholar]
  17. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  18. Jones S. N., Roe A. E., Donehower L. A., Bradley A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995 Nov 9;378(6553):206–208. doi: 10.1038/378206a0. [DOI] [PubMed] [Google Scholar]
  19. Leroy-Viard K., Vinit M. A., Lecointe N., Jouault H., Hibner U., Roméo P. H., Mathieu-Mahul D. Loss of TAL-1 protein activity induces premature apoptosis of Jurkat leukemic T cells upon medium depletion. EMBO J. 1995 May 15;14(10):2341–2349. doi: 10.1002/j.1460-2075.1995.tb07229.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lotem J., Sachs L. Hematopoietic cells from mice deficient in wild-type p53 are more resistant to induction of apoptosis by some agents. Blood. 1993 Aug 15;82(4):1092–1096. [PubMed] [Google Scholar]
  21. Lowe S. W., Ruley H. E., Jacks T., Housman D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993 Sep 24;74(6):957–967. doi: 10.1016/0092-8674(93)90719-7. [DOI] [PubMed] [Google Scholar]
  22. 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. 1993 Apr 29;362(6423):847–849. doi: 10.1038/362847a0. [DOI] [PubMed] [Google Scholar]
  23. Malcomson R. D., Oren M., Wyllie A. H., Harrison D. J. p53-independent death and p53-induced protection against apoptosis in fibroblasts treated with chemotherapeutic drugs. Br J Cancer. 1995 Oct;72(4):952–957. doi: 10.1038/bjc.1995.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Metz T., Harris A. W., Adams J. M. Absence of p53 allows direct immortalization of hematopoietic cells by the myc and raf oncogenes. Cell. 1995 Jul 14;82(1):29–36. doi: 10.1016/0092-8674(95)90049-7. [DOI] [PubMed] [Google Scholar]
  25. Michalovitz D., Halevy O., Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell. 1990 Aug 24;62(4):671–680. doi: 10.1016/0092-8674(90)90113-s. [DOI] [PubMed] [Google Scholar]
  26. Montes de Oca Luna R., Wagner D. S., Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995 Nov 9;378(6553):203–206. doi: 10.1038/378203a0. [DOI] [PubMed] [Google Scholar]
  27. Olson D. C., Marechal V., Momand J., Chen J., Romocki C., Levine A. J. Identification and characterization of multiple mdm-2 proteins and mdm-2-p53 protein complexes. Oncogene. 1993 Sep;8(9):2353–2360. [PubMed] [Google Scholar]
  28. Raff M. C. Social controls on cell survival and cell death. Nature. 1992 Apr 2;356(6368):397–400. doi: 10.1038/356397a0. [DOI] [PubMed] [Google Scholar]
  29. Sah V. P., Attardi L. D., Mulligan G. J., Williams B. O., Bronson R. T., Jacks T. A subset of p53-deficient embryos exhibit exencephaly. Nat Genet. 1995 Jun;10(2):175–180. doi: 10.1038/ng0695-175. [DOI] [PubMed] [Google Scholar]
  30. Schmid P., Lorenz A., Hameister H., Montenarh M. Expression of p53 during mouse embryogenesis. Development. 1991 Nov;113(3):857–865. doi: 10.1242/dev.113.3.857. [DOI] [PubMed] [Google Scholar]
  31. Sehgal P. B., Margulies L. Cell-type- and promoter-dependent ts phenotype of p53 Val135. Oncogene. 1993 Dec;8(12):3417–3419. [PubMed] [Google Scholar]
  32. 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]
  33. Symonds H., Krall L., Remington L., Saenz-Robles M., Lowe S., Jacks T., Van Dyke T. p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell. 1994 Aug 26;78(4):703–711. doi: 10.1016/0092-8674(94)90534-7. [DOI] [PubMed] [Google Scholar]
  34. Wagner A. J., Kokontis J. M., Hay N. Myc-mediated apoptosis requires wild-type p53 in a manner independent of cell cycle arrest and the ability of p53 to induce p21waf1/cip1. Genes Dev. 1994 Dec 1;8(23):2817–2830. doi: 10.1101/gad.8.23.2817. [DOI] [PubMed] [Google Scholar]
  35. Wagner A. J., Small M. B., Hay N. Myc-mediated apoptosis is blocked by ectopic expression of Bcl-2. Mol Cell Biol. 1993 Apr;13(4):2432–2440. doi: 10.1128/mcb.13.4.2432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Wahl A. F., Donaldson K. L., Fairchild C., Lee F. Y., Foster S. A., Demers G. W., Galloway D. A. Loss of normal p53 function confers sensitization to Taxol by increasing G2/M arrest and apoptosis. Nat Med. 1996 Jan;2(1):72–79. doi: 10.1038/nm0196-72. [DOI] [PubMed] [Google Scholar]
  37. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  38. 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]

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