Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development

• Published in: Oncogene Vol. 23; no. 55; pp. 8931 - 8940
• Main Authors: EISCHEN, Christine M, ALT, Jodi R, PENG WANG
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 25.11.2004; Nature Publishing Group
• Subjects: ADP-Ribosylation Factor 1 - genetics; ADP-Ribosylation Factor 1 - metabolism; Ageing, cell death; Alleles; Animals; Apoptosis; B-Lymphocytes - metabolism; Biological and medical sciences; Blotting, Southern; Blotting, Western; Cell cycle; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-Dependent Kinase Inhibitor p16; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Gamma Rays; Genes, p53; Genetic transformation; Haploinsufficiency; Hematologic and hematopoietic diseases; Latency; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes - metabolism; Lymphocytes B; Lymphoma; Lymphoma - genetics; Lymphoma - pathology; MDM2 protein; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Biological; Molecular and cellular biology; Mutation; Myc protein; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Proteome; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-mdm2; Sensitivity and Specificity; Sequence Analysis, DNA; Spleen - metabolism; Stoichiometry; Time Factors; Transcription, Genetic; Transgenes; Transgenic animals; Transgenic mice; Tumor suppressor genes; Tumor Suppressor Protein p14ARF - metabolism; Tumor Suppressor Protein p53 - metabolism; Tumors; Malignant hemopathy; Carcinogenesis; Lymphoma; p53; Allele; TP53 Gene; ARF; Lymphoproliferative syndrome; Myc; Development; Mdm2; Onc gene; Apoptosis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1208052

The tumor suppressor p19ARF inhibits Mdm2, which restricts the activity of p53. Complicated feedback and control mechanisms regulate ARF, Mdm2, and p53 interactions. Here we report that ARF haploinsufficiency completely rescued the p53-dependent effects of Mdm2 haploinsufficiency on B-cell development, survival, and transformation. In contrast to Mdm2+/- B cells, Mdm2+/- B cells deficient in ARF were similar to wild-type B cells in their rates of growth and apoptosis and activation of p53. Consequently, the profoundly reduced numbers of B cells in Mdm2+/-Emu-myc transgenic mice were restored to normal levels in ARF+/-Mdm2+/-Emu-myc transgenics. Additionally, ARF+/-Mdm2+/-Emu-myc transgenics developed lymphomas at rates analogous to those observed for wild-type Emu-myc transgenics, demonstrating that loss of one allele of ARF rescued the protracted lymphoma latency in Mdm2+/-Emu-myc transgenics. Importantly, in ARF+/-Mdm2+/-Emu-myc transgenic lymphomas, p53 was inactivated at the frequency observed in lymphomas of wild-type Emu-myc transgenics. Collectively, these results support a model whereby the stoichiometry of Mdm2 and ARF controls apoptosis and tumor development, which should have significant implications in the treatment of malignancies that have inactivated ARF.