The MMTV/c-myc transgene and p53 null alleles collaborate to induce T-cell lymphomas, but not mammary carcinomas in transgenic mice.
A number of properties of the cancer-related genes c-myc and p53 suggest that they might collaborate to induce tumorigenesis. To test this notion, we produced doubly heterozygotic mice bearing disrupted p53 alleles and a fusion transgene consisting of the mouse mammary tumor virus (MMTV) LTR and the oncogene c-myc. Mice bearing both the MMT/c-myc transgene and a single p53- allele develop very aggressive pre-T- and T-cell lymphomas with a significantly shorter latency than mice carrying either the p53- allele or the c-myc transgene alone. Moreover, every lymphoma occurring in these animals has lost or suffers an inactivation of its wild type p53 allele indicating that loss of p53 activity is necessary for this c-myc-accelerated lymphomagenesis. Nonetheless, p53 inactivation and expression of the MMTV/c-myc transgene are not sufficient for lymphoid transformation. Tumors that arise in homozygous p53- mice carrying the c-myc transgene are monoclonal, suggesting that at least one additional event is necessary for their transformation. Moreover, since mice bearing only the MMTV/c-myc transgene predominantly develop mammary carcinomas, it was surprising that the p53- allele failed to accelerate the incidence of mammary carcinomas. Further, in contrast to the lymphomas, only one in four mammary tumors that arose in the double heterozygotic mice had lost its wild type p53 allele. Apparently cell context influences the ability of c-myc and p53- to cooperate in inducing oncogenesis.
Elson
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A
Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Deng
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C
Campos-Torres
J
J
Donehower
L A
LA
Leder
P
P
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D017931:DNA Primers; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc; D016158:Genes, p53; D005838:Genotype; D006579:Heterozygote; D016399:Lymphoma, T-Cell / Q000235:genetics*; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D047428:Protein Kinase Inhibitors
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017931:DNA Primers; D047428:Protein Kinase Inhibitors