Tumor spectrum in ARF-deficient mice

Takehiko Kamijo, Sara Bodner, Esther Van De Kamp, David H. Randle, Charles J. Sherr

Research output: Contribution to journalArticle

289 Scopus citations

Abstract

The p19(ARF) product of the INK4a/ARF locus is induced in response to potentially oncogenic hyperproliferative signals and activates p53 by interfering with its negative regulator, Mdm2. Mice lacking ARF are highly prone to tumor development, and in this study, 80% of these animals spontaneously developed tumors and died within their first year of life. Mice that were heterozygous for ARF also developed tumors after a longer latency, whereas their wild-type littermates did not. In heterozygotes, tumor formation was accompanied by loss of the residual ARF allele and/or lack of ARF mRNA expression, implying that ARF can act as a canonical 'two-hit' tumor suppressor gene. Tumors occurred earlier in life in ARF-null animals that were neonatally irradiated or given dimethylbenzanthrene, and several animals treated with carcinogen simultaneously developed multiple forms of malignancy arising from distinct cell lineages. Although p53-null mice primarily develop lymphomas and fibrosarcomas, the frequency of these two tumor types was inverted in ARF-null animals, with undifferentiated sarcomas predominating in a 3:2 ratio; 28% of ARF-null animals developed carcinomas and tumors of the nervous system, which have been rarely observed in untreated p53-null mice. The longer latency of tumor formation in ARF-null versus p53-null mice, therefore, appears to enable a broader spectrum of tumors to emerge.

Original languageEnglish (US)
Pages (from-to)2217-2222
Number of pages6
JournalCancer Research
Volume59
Issue number9
StatePublished - May 1 1999

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kamijo, T., Bodner, S., Van De Kamp, E., Randle, D. H., & Sherr, C. J. (1999). Tumor spectrum in ARF-deficient mice. Cancer Research, 59(9), 2217-2222.