Abstract
Jab1, a co-activator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome, mediates degradation of the tumor suppressor p53 and p27(Kip1) and functions as a tumor promoter in different types of human cancer. In this study, we show that inhibition of Bcr-Abl oncogene by imatinib induces down-regulation of Jab1 in Bcr-Abl-positive K562, Ku812, and MEG01 leukemia cells suggesting Bcr-Abl may regulate Jab1 expression. Promoter deletion and mutation analysis indicate the Tcf-4/β-catenin and STAT1 binding sites located between the -405/-223 region of the human Jab1 promoter are important for the activation of Jab1 by Bcr-Abl. Double mutation of these two sites reverses the inhibitory effect of imatinib. Chromatin immunoprecipitation assay verifies the binding of β-catenin and STAT1 to human Jab1 promoter. Ectopic expression of dominant-negative Tcf-4 mutant significantly attenuates Jab1 expression while over-expression of β-catenin and STAT1 cooperatively up-regulates Jab1 promoter activity and mRNA expression. Our results also demonstrate that the AKT signaling pathway is involved in the regulation of Jab1 by Bcr-Abl because the AKT inhibitor LY294002 but not the ERK inhibitor PD98059 reduces Jab1 promoter activity and mRNA expression. Taken together, our results suggest that Bcr-Abl stimulates Jab1 expression via the cooperative interaction of β-catenin and STAT1 in leukemia cells.
Copyright © 2011 Wiley-Liss, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Benzamides
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COP9 Signalosome Complex
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Cell Line, Tumor
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Chromones / pharmacology
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Down-Regulation
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / metabolism*
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Humans
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Imatinib Mesylate
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Intracellular Signaling Peptides and Proteins / metabolism*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Morpholines / pharmacology
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Oncogene Protein v-akt / antagonists & inhibitors
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Peptide Hydrolases / metabolism*
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Piperazines / pharmacology
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Promoter Regions, Genetic / genetics
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Pyrimidines / pharmacology
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STAT1 Transcription Factor / metabolism*
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism
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beta Catenin / metabolism*
Substances
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Antineoplastic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Benzamides
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CTNNB1 protein, human
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Chromones
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Enzyme Inhibitors
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Flavonoids
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Intracellular Signaling Peptides and Proteins
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Morpholines
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Piperazines
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Pyrimidines
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STAT1 Transcription Factor
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STAT1 protein, human
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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beta Catenin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Imatinib Mesylate
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Fusion Proteins, bcr-abl
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Oncogene Protein v-akt
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Peptide Hydrolases
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COPS5 protein, human
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COP9 Signalosome Complex
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one