title: Bcr-Abl oncogene stimulates Jab1 expression via cooperative interaction of β-catenin and STAT1 in chronic myeloid leukemia cells.
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.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Kuei-Ting
authors.initials: KT
authors.lastname: Yang
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Wang
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Chen
authors.forename: Ming-Chuan
authors.initials: MC
authors.lastname: Hsu
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001549:Benzamides; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D010447:Peptide Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001549:Benzamides; C495270:CTNNB1 protein, human; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010879:Piperazines; D011743:Pyrimidines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D051058:Oncogene Protein v-akt; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one