title: The β-catenin E3 ubiquitin ligase SIAH-1 is regulated by CSN5/JAB1 in CRC cells.
abstract: COP9 signalosome subunit 5 (CSN5) plays a decisive role in cellular processes such as cell cycle regulation and apoptosis via promoting protein degradation, gene transcription, and nuclear export. CSN5 regulates cullin-RING-E3 ligase (CRL) activity through its deNEDDylase function. It is overexpressed in several tumor entities, but its role in colorectal cancer (CRC) is poorly understood. Wnt/β-catenin signaling is aberrant in most CRC cells, resulting in increased levels of oncogenic β-catenin and thus tumor progression. Under physiological conditions, β-catenin levels are tightly regulated by continuous proteasomal degradation. We recently showed that knockdown of CSN5 in model and CRC cells results in decreased (phospho)-β-catenin levels. Reduced β-catenin levels were associated with an attenuated proliferation rate of different CRC cell types after CSN5 knockdown. The canonical Wnt pathway involves degradation of β-catenin by a β-TrCP1-containing E3 ligase, but is mostly non-functional in CRC cells. We thus hypothesized that alternative β-catenin degradation mediated by SIAH-1 (seven in absentia homolog-1), is responsible for the effect of CSN5 on β-catenin signaling in CRC cells. We found that SIAH-1 plays an essential role in β-catenin degradation in HCT116 CRC cells and that CSN5 affects β-catenin target gene expression in these cells. Of note, CSN5 affected SIAH-1 mRNA and SIAH-1 protein levels. Moreover, β-catenin and SIAH-1 form protein complexes with CSN5 in HCT116 cells. Lastly, we demonstrate that CSN5 promotes SIAH-1 degradation in HCT116 and SW480 cells and that this is associated with its deNEDDylase activity. In conclusion, we have identified a CSN5/β-catenin/SIAH-1 interaction network that might control β-catenin degradation in CRC cells.
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: sjumpertz@ukaachen.de.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jumpertz
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: thennes@ukaachen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hennes
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: yasare@ukaachen.de.
authors.forename: Yaw
authors.initials: Y
authors.lastname: Asare
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: jvervoorts-weber@ukaachen.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Vervoorts
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: jbernhagen@ukaachen.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
authors.affiliation: Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address: anschuetz@ukaachen.de.
authors.forename: Anke K
authors.initials: AK
authors.lastname: Schütz
mesh_terms: D000075686:COP9 Signalosome Complex; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000075687:NEDD8 Protein; D009687:Nuclear Proteins / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014452:Ubiquitins; D051153:Wnt Proteins; D051176:beta Catenin; D003513:Cycloheximide; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex
keywords: COP9 signalosome/CSN; CSN5/JAB1; NEDD8; SIAH-1; Wnt pathway; β-catenin