title: New Insights Into the Mechanism of COP9 Signalosome-Cullin-RING Ubiquitin-Ligase Pathway Deregulation in Urological Cancers.
abstract: Urological cancers are a very common type of cancer worldwide and have alarming high incidence and mortality rates, especially in kidney cancers, illustrate the urgent need for new therapeutic targets. Recent publications point to a deregulated COP9 signalosome (CSN)-cullin-RING ubiquitin-ligase (CRL) pathway which is here considered and investigated as potential target in urological cancers with strong focus on renal cell carcinomas (RCC). The CSN forms supercomplexes with CRLs in order to preserve protein homeostasis and was found deregulated in several cancer types. Examination of selected CSN-CRL pathway components in RCC patient samples and four RCC cell lines revealed an interesting deregulated p27(Kip1)-Skp2-CAND1 axis and two p27(Kip1) point mutations in 786-O cells; p27(Kip1)V109G and p27(Kip1)I119T. The p27(Kip1) mutants were detected in patients with RCC and appear to be responsible for an accelerated growth rate in 786-O cells. The occurrence of p27(Kip1)V109G and p27(Kip1)I119T in RCC makes the CSN-CRL pathway an attractive therapeutic target.
authors.affiliation: Department of General, Visceral, Vascular and Thoracic Surgery, Division of Molecular Biology, Charité-Universitätsmedizin, Berlin, Germany; Berlin Institute for Urological Research, Berlin, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Gummlich
authors.affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Kähne
authors.affiliation: Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Magdeburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Naumann
authors.affiliation: Department of Pathology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Ergin
authors.initials: E
authors.lastname: Kilic
authors.affiliation: Berlin Institute for Urological Research, Berlin, Germany; Department of Urology, Charité-Universitätsmedizin, Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Jung
authors.affiliation: Department of General, Visceral, Vascular and Thoracic Surgery, Division of Molecular Biology, Charité-Universitätsmedizin, Berlin, Germany. Electronic address: wolfgang.dubiel@charite.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dubiel
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; C584471:CULL-RING ligase, human; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex
keywords: COP9 signalosome; cullin-RING ubiquitin ligase; mutants; p27(Kip1); polymorphism; therapeutic target; urological cancer