title: Deregulation of the COP9 signalosome-cullin-RING ubiquitin-ligase pathway: mechanisms and roles in urological cancers.
abstract: The COP9 signalosome (CSN)-cullin-RING ubiquitin (Ub)-ligase (CRL) pathway is a prominent segment of the Ub proteasome system (UPS). It specifically ubiquitinates proteins and targets them for proteolytic elimination. As part of the UPS it maintains essential cellular processes including cell cycle progression, DNA repair, antigen processing and signal transduction. The CSN-CRL pathway consists of the CSN possessing eight subunits (CSN1-CSN8) and one CRL consisting of a cullin, a RING-domain protein and a substrate recognition subunit (SRS). In human cells approximately 250 CRLs exist each of which interacting with a specific set of substrates and the CSN. The CSN-CRL interplay determines the activity and specificity of CRL ubiquitination. The removal of the Ub-like protein Nedd8 from the CRL component cullin by the CSN (deneddylation) reduces the ubiquitinating activity and at the same time enables reassembly of CRLs in order to adapt to substrate specificity requirements. On the other hand, CRLs as well as substrates negatively influence the deneddylating activity of the CSN. In recent years evidence accumulated that deregulation of the CSN-CRL pathway can cause cancer. Here we review current knowledge on modifications of CSN and CRL components including CSN subunits, SRSs and cullins causing tumorigenesis with emphasis on urological neoplasia. The CSN-CRL pathway is a target of tumor-viruses as well as of a multitude of miRNAs. Recently evaluated miRNAs altered in urological cancers might have impact on the CSN-CRL pathway which has to be analyzed in future experiments. We propose that the pathway is a suitable target for future tumor therapy.
authors.affiliation: Department of General, Visceral, Vascular and Thoracic Surgery, Division of Molecular Biology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Gummlich
authors.forename: Anja
authors.initials: A
authors.lastname: Rabien
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dubiel
mesh_terms: D000075686:COP9 Signalosome Complex; D063646:Carcinogenesis / Q000378:metabolism; D002453:Cell Cycle; D044842:Cullin Proteins / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D046912:Multiprotein Complexes / Q000378:metabolism*; D000075687:NEDD8 Protein; D010447:Peptide Hydrolases / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D057149:Ubiquitinated Proteins; D054875:Ubiquitination; D014452:Ubiquitins; D014571:Urologic Neoplasms / Q000378:metabolism*
chemical_list: C486317:CAND1 protein, human; D044842:Cullin Proteins; D035683:MicroRNAs; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D014157:Transcription Factors; D057149:Ubiquitinated Proteins; D014452:Ubiquitins; D044843:SKP Cullin F-Box Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex