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

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.