Abstract
Nutlin3a is a small-molecule antagonist of MDM2 that promotes non-genotoxic activation of p53 through p53 protein stabilization and transactivation of p53 target genes. Nutlin3a is the forerunner of a class of cancer therapeutics that have reached clinical trials. Using transgenic and gene-targeted mouse models lacking the critical p53 target genes, p21, Puma, and Noxa, we found that only loss of PUMA conferred profound protection against Nutlin3a-induced killing in both non-transformed lymphoid cells and Eμ-Myc lymphomas in vitro and in vivo. CRISPR/Cas9-mediated targeting of the PUMA gene rendered human hematopoietic cancer cell lines markedly resistant to Nutlin3a-induced cell death. These results demonstrate that PUMA-mediated apoptosis, but not p21-mediated cell-cycle arrest or senescence, is a critical determinant of the therapeutic response to non-genotoxic p53 activation by Nutlin3a. Importantly, in human cancer, PUMA expression may predict patient responses to treatment with MDM2 antagonists.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / genetics*
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Apoptosis Regulatory Proteins / metabolism
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CRISPR-Cas Systems
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Cell Cycle Checkpoints
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Disease Models, Animal
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic*
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Humans
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Imidazoles / pharmacology*
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Lymphoma / drug therapy*
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Lymphoma / genetics
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Lymphoma / metabolism
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Lymphoma / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Piperazines / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / agonists
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Imidazoles
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PUMA protein, mouse
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Piperazines
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Pmaip1 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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nutlin 3
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2