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¹ College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
² Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
³ Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Tainan 701, Taiwan
⁴ National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Kaohsiung 804, Taiwan

(Correspondence should be addressed to W-C Hung, Institute of Biomedical Sciences, National Sun Yat-Sen University, No.70, Lion-Hai Road, Kaohsiung 804, Taiwan; Email: hung1228{at}ms10.hinet.net)

Jab1 is a co-activator of activating protein-1 (AP-1) transcription factor and the fifth subunit of the constitutive photomorphogenesis 9 (COP9) signalosome, which has been shown to mediate nuclear exportation and ubiquitin-dependent degradation of the tumor suppressor p27^Kip1. Jab1 is overexpressed in several types of human cancer. However, de-regulation of Jab1 gene expression in cancer cells is largely unclear. In this study, we reported that expression of Jab1 was stimulated by HER-2/neu oncogene via transcriptional activation. Promoter deletion and mutation analysis indicated that HER-2/neu stimulated Jab1 via the T cell factor (TCF) binding site located at the –380/–368 region of the human Jab1 promoter. DNA affinity precipitation assay and chromatin immunoprecipitation assay verified that binding of ß-catenin and TCF-4 to this consensus site was increased by HER-2/neu. In addition, dominant-negative mutant of TCF significantly attenuated the stimulatory effect of HER-2/neu. We also demonstrated that HER-2/neu increased ß-catenin/TCF-mediated Jab1 expression via the AKT signaling pathway because chemical inhibitor or dominant-negative mutant of AKT effectively attenuated the stimulatory action of HER-2/neu. IGF-I, which is a well-known AKT activator, also up-regulated the expression of Jab1 in NIH/3T3 and MCF-7 cells. Knockdown of Jab1 by small interfering RNA (siRNA) preferentially inhibited proliferation of HER-2/neu-overexpressing breast cancer cells. Taken together, our results suggest that HER-2/neu transcriptionally activates Jab1 expression to promote proliferation of breast cancer cells.

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				M.-C. Hsu, C.-C. Huang, H.-C. Chang, T.-H. Hu, and W.-C. Hung Overexpression of Jab1 in Hepatocellular Carcinoma and Its Inhibition by Peroxisome Proliferator-Activated Receptor{gamma} Ligands In vitro and In vivo Clin. Cancer Res., July 1, 2008; 14(13): 4045 - 4052. [Abstract] [Full Text] [PDF]