HER-2/neu transcriptionally activates Jab1 expression via the AKT/beta-catenin pathway in breast cancer cells.
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 beta-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 beta-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.
Mesh Terms:
Animals, Binding Sites, Breast Neoplasms, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Mice, NIH 3T3 Cells, Oncogene Protein v-akt, Peptide Hydrolases, Promoter Regions, Genetic, RNA, Small Interfering, Receptor, erbB-2, Signal Transduction, TCF Transcription Factors, Transcriptional Activation, Transfection, Tumor Cells, Cultured, beta Catenin
Animals, Binding Sites, Breast Neoplasms, Cell Proliferation, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Mice, NIH 3T3 Cells, Oncogene Protein v-akt, Peptide Hydrolases, Promoter Regions, Genetic, RNA, Small Interfering, Receptor, erbB-2, Signal Transduction, TCF Transcription Factors, Transcriptional Activation, Transfection, Tumor Cells, Cultured, beta Catenin
Endocr. Relat. Cancer
Date: Sep. 01, 2007
PubMed ID: 17914096
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