An RNAi screen identifies USP2 as a factor required for TNF-α-induced NF-κB signaling
Marie Metzig
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorDorothee Nickles
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorChristina Falschlehner
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorJudith Lehmann-Koch
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorBeate K. Straub
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorWilfried Roth
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Michael Boutros
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Tel.: +49-6221-421951, Fax: +49-6221-421959
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, ImNeuenheimerFeld 580, 69120 Heidelberg, GermanySearch for more papers by this authorMarie Metzig
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorDorothee Nickles
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorChristina Falschlehner
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Search for more papers by this authorJudith Lehmann-Koch
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorBeate K. Straub
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorWilfried Roth
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Michael Boutros
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, Heidelberg, Germany
Tel.: +49-6221-421951, Fax: +49-6221-421959
German Cancer Research Center (DKFZ), Division of Signaling and Functional Genomics, and Department for Cell and Molecular Biology, Faculty for Medicine Mannheim, University of Heidelberg, ImNeuenheimerFeld 580, 69120 Heidelberg, GermanySearch for more papers by this authorAbstract
Tumor necrosis factor α (TNF-α) signaling pathways play important roles during tumorigenesis and inflammation. Ubiquitin-dependent processes are central to the regulation of TNF-α and nuclear factor κB (NF-κB) signaling. We performed a targeted siRNA screen for ubiquitin-specific proteases (USPs) and identified USP2 as a modulator of TNF-α-induced NF-κB signaling. We showed that USP2 is required for the phosphorylation of IκB, nuclear translocation of NF-κB and expression of NF-κB-dependent target genes and IL-8 secretion. Our study also provides evidence for isoform-specific functions of USP2. The immunohistochemical analysis of breast carcinomas revealed that USP2 expression is frequently downregulated. Together, our results implicate USP2 as a novel positive regulator of TNF-α-induced NF-κB signaling and show that its expression is altered in tumor cells.
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