Abstract
Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Aurora Kinase A
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Aurora Kinase B
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Aurora Kinases
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology*
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BALB 3T3 Cells
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Blotting, Western
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Cell Proliferation
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Cell Transformation, Neoplastic
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Cells, Cultured
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Chromatin Immunoprecipitation
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Electrophoretic Mobility Shift Assay
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Gene Expression Profiling
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Gene Expression Regulation, Enzymologic / physiology*
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Humans
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Immunoenzyme Techniques
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Luciferases / metabolism
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism
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Lymphoma, B-Cell / pathology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / 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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RNA, Messenger / genetics
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Transfection
Substances
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Biomarkers, Tumor
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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RNA, Small Interfering
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Luciferases
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AURKA protein, human
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AURKB protein, human
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Aurka protein, mouse
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Aurkb protein, mouse
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Aurora Kinase A
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Aurora Kinase B
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Aurora Kinases
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Protein Serine-Threonine Kinases