Dissecting p53 tumor suppressor functions in vivo.
Although the p53 tumor suppressor acts in a plethora of processes that influence cellular proliferation and survival, it remains unclear which p53 functions are essential for tumor suppression and, as a consequence, are selected against during tumor development. Using a mouse model harboring primary, genetically modified myc-driven lymphomas, we show that disruption of apoptosis downstream of p53 by Bcl2 or a dominant-negative caspase 9 confers-like p53 loss-a selective advantage, and completely alleviates pressure to inactivate p53 during lymphomagenesis. Despite their p53-null-like aggressive phenotype, apoptosis-defective lymphomas that retain intact p53 genes do not display the checkpoint defects and gross aneuploidy that are characteristic of p53 mutant tumors. Therefore, apoptosis is the only p53 function selected against during lymphoma development, whereas defective cell-cycle checkpoints and aneuploidy are mere byproducts of p53 loss.
Schmitt
Clemens A
CA
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
Fridman
Jordan S
JS
Yang
Meng
M
Baranov
Eugene
E
Hoffman
Robert M
RM
Lowe
Scott W
SW
D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053453:Caspase 9; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D005799:Genes, Dominant / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D018816:Genes, cdc / Q000502:physiology; D016259:Genes, myc / Q000502:physiology; D049452:Green Fluorescent Proteins; D006720:Homozygote; D006801:Humans; D008164:Luminescent Proteins; D008168:Lung / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D011003:Ploidies; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C493956:CDKN1A protein, human; D061945:Caspase Inhibitors; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003574:Cytochrome c Group; D008164:Luminescent Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D049452:Green Fluorescent Proteins; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9