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

286 Citations (Scopus)

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

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Neoplasms
Nervous System Neoplasms
Fibrosarcoma
Cell Lineage
Heterozygote
Tumor Suppressor Genes
Sarcoma
Carcinogens
Lymphoma
Alleles
Carcinoma
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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.

Tumor spectrum in ARF-deficient mice. / Kamijo, Takehiko; Bodner, Sara; Van De Kamp, Esther; Randle, David H.; Sherr, Charles J.

In: Cancer Research, Vol. 59, No. 9, 01.05.1999, p. 2217-2222.

Research output: Contribution to journalArticle

Kamijo, T, Bodner, S, Van De Kamp, E, Randle, DH & Sherr, CJ 1999, 'Tumor spectrum in ARF-deficient mice', Cancer Research, vol. 59, no. 9, pp. 2217-2222.
Kamijo T, Bodner S, Van De Kamp E, Randle DH, Sherr CJ. Tumor spectrum in ARF-deficient mice. Cancer Research. 1999 May 1;59(9):2217-2222.
Kamijo, Takehiko ; Bodner, Sara ; Van De Kamp, Esther ; Randle, David H. ; Sherr, Charles J. / Tumor spectrum in ARF-deficient mice. In: Cancer Research. 1999 ; Vol. 59, No. 9. pp. 2217-2222.
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