Mdm2 overexpression and p73 loss exacerbate genomic instability and dampen apoptosis, resulting in B-cell lymphoma.
Many human tumors express high levels of the p53 inhibitor Mdm2, resulting from amplification of the Mdm2 locus or aberrant post-translational regulation of the Mdm2 protein. While the importance of Mdm2 in regulating p53 is clear, Mdm2 also has p53-independent roles. For example, overexpression of Mdm2 results in genomic instability in a p53-independent manner. In addition, Mdm2 has many additional binding partners, some of which, such as the tumor suppressor p73, have also been implicated in genomic instability. In this study, cells and tumors with Mdm2 overexpression and p73 loss exhibit increased genomic instability as compared with either alteration alone and cooperate in development of B-cell lymphomagenesis. Cytogenetic analysis of mouse embryonic fibroblasts and pre-malignant B cells demonstrates that loss of p73 exacerbates the chromosome breaks and fusions observed in Mdm2(Tg) cells. B-cell lymphomas from Mdm2(Tg);p73(+/-) mice retain the remaining p73 allele, exhibit elevated levels of the antiapoptotic protein Bcl2 and thus dampen apoptosis. In summary, Mdm2 overexpression and p73 loss cooperate in genomic instability and tumor development, indicating that the oncogenic function of Mdm2 is a combined effect of inhibiting p53 and p73 functions. Given that p73 is lost or silenced in human B-cell lymphomas, the Mdm2(Tg);p73(+/-) mouse serves as a model for human disease and may provide additional insight into the pathways that contribute to B-cell lymphomagenesis.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M F
MF
Riley
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M J
MJ
You
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
A S
AS
Multani
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
G
G
Lozano
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis* / Q000235:genetics; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2