Bcr-Abl oncogene stimulates Jab1 expression via cooperative interaction of β-catenin and STAT1 in chronic myeloid leukemia cells

J Cell Physiol. 2011 Nov;226(11):2849-56. doi: 10.1002/jcp.22633.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • Benzamides
  • COP9 Signalosome Complex
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imatinib Mesylate
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Morpholines / pharmacology
  • Oncogene Protein v-akt / antagonists & inhibitors
  • Peptide Hydrolases / metabolism*
  • Piperazines / pharmacology
  • Promoter Regions, Genetic / genetics
  • Pyrimidines / pharmacology
  • STAT1 Transcription Factor / metabolism*
  • Transcription Factor 4
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Benzamides
  • CTNNB1 protein, human
  • Chromones
  • Enzyme Inhibitors
  • Flavonoids
  • Intracellular Signaling Peptides and Proteins
  • Morpholines
  • Piperazines
  • Pyrimidines
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • TCF4 protein, human
  • Transcription Factor 4
  • Transcription Factors
  • beta Catenin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Oncogene Protein v-akt
  • Peptide Hydrolases
  • COPS5 protein, human
  • COP9 Signalosome Complex
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one