Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Feb;17(2):723–731. doi: 10.1128/mcb.17.2.723

Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53.

J E Hundley 1, S K Koester 1, D A Troyer 1, S G Hilsenbeck 1, M A Subler 1, J J Windle 1
PMCID: PMC231798  PMID: 9001226

Abstract

We have used an in vivo tumor model to evaluate the consequences of p53 tumor suppressor protein deficiency in a tissue-specific context. By breeding MMTV-ras transgenic mice, which are highly susceptible to the development of mammary and salivary tumors, with p53(-/-) mice, we generated three classes of animals which contained the MMTV-ras transgene but differed in their p53 functional status (ras/p53(+/+), ras/p53(+/-), or ras/p53(-/-)). ras/p53(-/-) mice developed tumors more rapidly than animals of the other two genotypes; however, the distribution of tumors was unexpectedly altered. Whereas the most frequently observed tumors in ras/p53(+/+) and ras/p53(+/-) mice were of mammary origin, ras/p53(-/-) mice developed primarily salivary tumors. In addition, the mammary and salivary tumors from ras/p53(-/-) mice consistently exhibited a number of unfavorable characteristics, including higher histologic grades, increased growth rates, and extensive genomic instability and heterogeneity, relative to tumors from ras/p53(+/+) mice. Interestingly, the increased growth rates of ras/p53(-/-) tumors appear to be due to impaired cell cycle regulation rather than decreased apoptosis, suggesting that p53-mediated tumor suppression can occur independent of its role in apoptosis.

Full Text

The Full Text of this article is available as a PDF (654.2 KB).

Selected References

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

  1. Arends M. J., McGregor A. H., Toft N. J., Brown E. J., Wyllie A. H. Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability. Br J Cancer. 1993 Dec;68(6):1127–1133. doi: 10.1038/bjc.1993.492. [DOI] [PMC free article] [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. Auer G. U., Heselmeyer K. M., Steinbeck R. G., Munck-Wikland E., Zetterberg A. D. The relationship between aneuploidy and p53 overexpression during genesis of colorectal adenocarcinoma. Virchows Arch. 1994;424(4):343–347. doi: 10.1007/BF00190554. [DOI] [PubMed] [Google Scholar]
  4. Billadeau D., Jelinek D. F., Shah N., LeBien T. W., Van Ness B. Introduction of an activated N-ras oncogene alters the growth characteristics of the interleukin 6-dependent myeloma cell line ANBL6. Cancer Res. 1995 Aug 15;55(16):3640–3646. [PubMed] [Google Scholar]
  5. 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]
  6. Clarke A. R., Cummings M. C., Harrison D. J. Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy. Oncogene. 1995 Nov 2;11(9):1913–1920. [PubMed] [Google Scholar]
  7. Debbas M., White E. Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B. Genes Dev. 1993 Apr;7(4):546–554. doi: 10.1101/gad.7.4.546. [DOI] [PubMed] [Google Scholar]
  8. Donehower L. A., Godley L. A., Aldaz C. M., Pyle R., Shi Y. P., Pinkel D., Gray J., Bradley A., Medina D., Varmus H. E. Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes Dev. 1995 Apr 1;9(7):882–895. doi: 10.1101/gad.9.7.882. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Elledge R. M., Clark G. M., Fuqua S. A., Yu Y. Y., Allred D. C. p53 protein accumulation detected by five different antibodies: relationship to prognosis and heat shock protein 70 in breast cancer. Cancer Res. 1994 Jul 15;54(14):3752–3757. [PubMed] [Google Scholar]
  11. Elledge R. M., Fuqua S. A., Clark G. M., Pujol P., Allred D. C. William L. McGuire Memorial Symposium. The role and prognostic significance of p53 gene alterations in breast cancer. Breast Cancer Res Treat. 1993;27(1-2):95–102. doi: 10.1007/BF00683196. [DOI] [PubMed] [Google Scholar]
  12. Elson A., Deng C., Campos-Torres J., Donehower L. A., Leder P. The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice. Oncogene. 1995 Jul 6;11(1):181–190. [PubMed] [Google Scholar]
  13. 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]
  14. Fujimoto K., Yamada Y., Okajima E., Kakizoe T., Sasaki H., Sugimura T., Terada M. Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res. 1992 Mar 15;52(6):1393–1398. [PubMed] [Google Scholar]
  15. 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]
  16. Hansen R., Reddel R., Braithwaite A. The transforming oncoproteins determine the mechanism by which p53 suppresses cell transformation: pRb-mediated growth arrest or apoptosis. Oncogene. 1995 Dec 21;11(12):2535–2545. [PubMed] [Google Scholar]
  17. 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]
  18. Harvey M., Sands A. T., Weiss R. S., Hegi M. E., Wiseman R. W., Pantazis P., Giovanella B. C., Tainsky M. A., Bradley A., Donehower L. A. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene. 1993 Sep;8(9):2457–2467. [PubMed] [Google Scholar]
  19. Heitjan D. F., Manni A., Santen R. J. Statistical analysis of in vivo tumor growth experiments. Cancer Res. 1993 Dec 15;53(24):6042–6050. [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Hsu B., Marin M. C., el-Naggar A. K., Stephens L. C., Brisbay S., McDonnell T. J. Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis. Oncogene. 1995 Jul 6;11(1):175–179. [PubMed] [Google Scholar]
  23. Iwaya K., Tsuda H., Hiraide H., Tamaki K., Tamakuma S., Fukutomi T., Mukai K., Hirohashi S. Nuclear p53 immunoreaction associated with poor prognosis of breast cancer. Jpn J Cancer Res. 1991 Jul;82(7):835–840. doi: 10.1111/j.1349-7006.1991.tb02710.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jerry D. J., Ozbun M. A., Kittrell F. S., Lane D. P., Medina D., Butel J. S. Mutations in p53 are frequent in the preneoplastic stage of mouse mammary tumor development. Cancer Res. 1993 Jul 15;53(14):3374–3381. [PubMed] [Google Scholar]
  25. Krishan A. Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining. J Cell Biol. 1975 Jul;66(1):188–193. doi: 10.1083/jcb.66.1.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Liebermann D. A., Hoffman B., Steinman R. A. Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways. Oncogene. 1995 Jul 6;11(1):199–210. [PubMed] [Google Scholar]
  27. Lin D., Shields M. T., Ullrich S. J., Appella E., Mercer W. E. Growth arrest induced by wild-type p53 protein blocks cells prior to or near the restriction point in late G1 phase. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9210–9214. doi: 10.1073/pnas.89.19.9210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lin H. J., Eviner V., Prendergast G. C., White E. Activated H-ras rescues E1A-induced apoptosis and cooperates with E1A to overcome p53-dependent growth arrest. Mol Cell Biol. 1995 Aug;15(8):4536–4544. doi: 10.1128/mcb.15.8.4536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lin Y., Benchimol S. Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest. Mol Cell Biol. 1995 Nov;15(11):6045–6054. doi: 10.1128/mcb.15.11.6045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Livingstone L. R., White A., Sprouse J., Livanos E., Jacks T., Tlsty T. D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell. 1992 Sep 18;70(6):923–935. doi: 10.1016/0092-8674(92)90243-6. [DOI] [PubMed] [Google Scholar]
  31. Lowe S. W., Ruley H. E. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 1993 Apr;7(4):535–545. doi: 10.1101/gad.7.4.535. [DOI] [PubMed] [Google Scholar]
  32. Martinez J., Georgoff I., Martinez J., Levine A. J. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Genes Dev. 1991 Feb;5(2):151–159. doi: 10.1101/gad.5.2.151. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Okan I., Wang Y., Chen F., Hu L. F., Imreh S., Klein G., Wiman K. G. The EBV-encoded LMP1 protein inhibits p53-triggered apoptosis but not growth arrest. Oncogene. 1995 Sep 21;11(6):1027–1031. [PubMed] [Google Scholar]
  35. Qin X. Q., Livingston D. M., Kaelin W. G., Jr, Adams P. D. Deregulated transcription factor E2F-1 expression leads to S-phase entry and p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10918–10922. doi: 10.1073/pnas.91.23.10918. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Sala A., Casella I., Grasso L., Bellon T., Reed J. C., Miyashita T., Peschle C. Apoptotic response to oncogenic stimuli: cooperative and antagonistic interactions between c-myb and the growth suppressor p53. Cancer Res. 1996 May 1;56(9):1991–1996. [PubMed] [Google Scholar]
  38. Shan B., Lee W. H. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis. Mol Cell Biol. 1994 Dec;14(12):8166–8173. doi: 10.1128/mcb.14.12.8166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. 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]
  40. Sinn E., Muller W., Pattengale P., Tepler I., Wallace R., Leder P. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell. 1987 May 22;49(4):465–475. doi: 10.1016/0092-8674(87)90449-1. [DOI] [PubMed] [Google Scholar]
  41. Stewart T. A., Pattengale P. K., Leder P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell. 1984 Oct;38(3):627–637. doi: 10.1016/0092-8674(84)90257-5. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Thor A. D., Moore DH I. I., Edgerton S. M., Kawasaki E. S., Reihsaus E., Lynch H. T., Marcus J. N., Schwartz L., Chen L. C., Mayall B. H. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst. 1992 Jun 3;84(11):845–855. doi: 10.1093/jnci/84.11.845. [DOI] [PubMed] [Google Scholar]
  44. Toffoli G., Doglioni C., Cernigoi C., Frustaci S., Perin T., Canal B., Boiocchi M. P53 overexpression in human soft tissue sarcomas: relation to biological aggressiveness. Ann Oncol. 1994 Feb;5(2):167–172. doi: 10.1093/oxfordjournals.annonc.a058771. [DOI] [PubMed] [Google Scholar]
  45. 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]
  46. Wyllie A. H., Rose K. A., Morris R. G., Steel C. M., Foster E., Spandidos D. A. Rodent fibroblast tumours expressing human myc and ras genes: growth, metastasis and endogenous oncogene expression. Br J Cancer. 1987 Sep;56(3):251–259. doi: 10.1038/bjc.1987.186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Yin Y., Tainsky M. A., Bischoff F. Z., Strong L. C., Wahl G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell. 1992 Sep 18;70(6):937–948. doi: 10.1016/0092-8674(92)90244-7. [DOI] [PubMed] [Google Scholar]
  48. 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]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES