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 p27Kip1 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. J. Cell. Physiol. 226: 2849–2856, 2011. © 2011 Wiley‐Liss, Inc.