Tumor spectrum in ARF-deficient mice.
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.
Kamijo
T
T
Howard Hughes Medical Institute, and Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Bodner
S
S
van de Kamp
E
E
Randle
D H
DH
Sherr
C J
CJ
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002277:Carcinoma / Q000209:etiology / Q000235:genetics; D019070:Cell Lineage; D003043:Cocarcinogenesis; D018450:Disease Progression; D005260:Female; D005354:Fibrosarcoma / Q000209:etiology / Q000235:genetics; D017353:Gene Deletion; D016158:Genes, p53; D005838:Genotype; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics*; D009380:Neoplasms, Nerve Tissue / Q000209:etiology / Q000235:genetics; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051736:Proto-Oncogene Proteins c-mdm2; D013997:Time Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2