Abstract
Checkpoints that control Myc-mediated proliferation and apoptosis are bypassed during tumorigenesis. Genes encoding polyamine biosynthetic enzymes are overexpressed in B cells from E mu-Myc transgenic mice. Here, we report that disabling one of these Myc targets, Ornithine decarboxylase (Odc), abolishes Myc-induced suppression of the Cdk inhibitors p21(Cip1) and p27(Kip1), thereby impairing Myc's proliferative, but not apoptotic, response. Moreover, lymphoma development was markedly delayed in E mu-Myc;Odc(+/-) transgenic mice and in E mu-Myc mice treated with the Odc inhibitor difluoromethylornithine (DFMO). Strikingly, tumors ultimately arising in E mu-Myc;Odc(+/-) transgenics lacked deletions of Arf, suggesting that targeting Odc forces other routes of transformation. Therefore, Odc is a critical Myc transcription target that regulates checkpoints that guard against tumorigenesis and is an effective target for cancer chemoprevention.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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B-Lymphocytes / chemistry
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B-Lymphocytes / drug effects
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B-Lymphocytes / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinase Inhibitor p27
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Eflornithine / pharmacology
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Gene Expression / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Heterozygote
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Lymphoma / drug therapy
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Lymphoma / genetics
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Lymphoma / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Mutant Strains
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Mice, Transgenic
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Organ Size / drug effects
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Ornithine Decarboxylase / genetics
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Ornithine Decarboxylase / metabolism*
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Ornithine Decarboxylase Inhibitors
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Polyamines / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Spleen / pathology
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Survival Rate
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Tumor Suppressor Protein p14ARF / genetics
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Tumor Suppressor Protein p14ARF / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Cdkn1a protein, mouse
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Cdkn1b protein, mouse
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Cdkn2a protein, mouse
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Myc protein, mouse
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Ornithine Decarboxylase Inhibitors
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Polyamines
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Proto-Oncogene Proteins c-myc
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Ornithine Decarboxylase
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Eflornithine