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...

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Bibliographic Details
Published in:Cancer cell 2002-04, Vol.1 (3), p.289-298
Main Authors: Schmitt, Clemens A, Fridman, Jordan S, Yang, Meng, Baranov, Eugene, Hoffman, Robert M, Lowe, Scott W
Format: Article
Language:English
Subjects:
Aneuploidy
Animals
Apoptosis - physiology
Caspase 9
Caspase Inhibitors
Cell Cycle - physiology
Cell Division - physiology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins - metabolism
Cytochrome c Group - metabolism
Gene Expression Regulation, Neoplastic - genetics
Gene Expression Regulation, Neoplastic - physiology
Genes, cdc - physiology
Genes, Dominant - physiology
Genes, myc - physiology
Genes, Tumor Suppressor - physiology
Green Fluorescent Proteins
Homozygote
Humans
Luminescent Proteins
Lung - pathology
Lymphoma - metabolism
Lymphoma - pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mutation - genetics
Neoplasms, Experimental - metabolism
Neoplasms, Experimental - pathology
Ploidies
Proto-Oncogene Proteins c-bcl-2 - metabolism
Tumor Suppressor Protein p53 - physiology
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Summary: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.
ISSN:1535-6108
1878-3686
DOI:10.1016/S1535-6108(02)00047-8