Jab1 is overexpressed in human breast cancer and is a downstream target for HER-2/neu.
Jab1 is a coactivator of AP-1 transcription factor and the fifth subunit of the COP9 signalosome. This protein is a potential oncogene and is involved in the mediation of nuclear exportation and degradation of the tumor suppressor p27(Kip1). However, control of Jab1 gene expression and its de-regulation in cancer cells are largely unknown. In this study, we demonstrated that Jab1 is overexpressed in 53 (80.3%) of a series of 66 human breast tumor tissues. In addition, its expression is significantly correlated with HER-2/neu overexpression (P=0.0318). HER-2/neu-overexpressing MDA-MB-453 human breast cancer cells exhibited higher expression of Jab1 than that of MCF-7 breast cancer cells. Promoter activity assay suggested that HER-2/neu oncogene upregulated Jab1 via transcriptional activation. Inhibition of HER-2/neu activity by Herceptin or AG825 significantly attenuated Jab1 expression in HER-2/neu-overexpressing MDA-MB-453 cells. On the contrary, ectopic expression of HER-2/neu stimulated Jab1 expression in MCF-7 cells. Knockdown of Jab1 expression by siRNA resulted in p27(Kip1) upregulation and G1 growth arrest in Jab1-overexpressing MDA-MB-453 cells. Taken together, our results suggest that Jab1 is a downstream target for HER-2/neu and its overexpression is linked with HER-2/neu expression in breast cancer.
Hsu
Ming-Chuan
MC
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chai
Chee-Yin
CY
Hou
Ming-Feng
MF
Chang
Hui-Chiu
HC
Chen
Wan-Tzu
WT
Hung
Wen-Chun
WC
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D000075686:COP9 Signalosome Complex; D047908:Intracellular Signaling Peptides and Proteins; D010447:Peptide Hydrolases; D018719:Erb-b2 Receptor Tyrosine Kinases; C501488:COPS5 protein, human