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Published on: May 14, 2013
Tumor spectrum in ARF-deficient mice
T Kamijo1, S Bodner, E van de Kamp
1Howard Hughes Medical Institute, and Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
The p19ARF 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.
Insights
The tumor suppressor p19ARF, a key regulator of p53, prevents cancer. Mice lacking ARF rapidly develop tumors, demonstrating its critical role in tumor suppression and cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The INK4a/ARF locus encodes p19ARF, a protein induced by hyperproliferative signals.
- p19ARF activates p53 by inhibiting its negative regulator, Mdm2.
- Loss of ARF function is implicated in tumor development.
Purpose of the Study:
- To investigate the role of p19ARF as a tumor suppressor.
- To characterize tumor development in ARF-deficient mice.
- To compare tumor spectrum in ARF-null versus p53-null mice.
Main Methods:
- Analysis of spontaneous tumor development in ARF-null and heterozygous mice.
- Assessment of ARF allele loss and mRNA expression in tumors.
- Evaluation of tumor incidence and latency in carcinogen-treated ARF-null mice.
- Comparison of tumor types in ARF-null and p53-null mice.
Main Results:
- 80% of ARF-null mice developed tumors and died within the first year.
- ARF-heterozygous mice developed tumors with longer latency, showing loss of the remaining ARF allele.
- Carcinogen exposure accelerated tumor formation in ARF-null mice, leading to multiple malignancies.
- ARF-null mice exhibited an inverted tumor spectrum compared to p53-null mice, with a higher incidence of sarcomas, carcinomas, and nervous system tumors.
Conclusions:
- ARF functions as a canonical "two-hit" tumor suppressor gene.
- Loss of ARF predisposes to a broad spectrum of tumors, including those rarely seen in p53-null mice.
- The latency of tumor formation in ARF-null mice allows for a wider range of malignancies to emerge.
