title: Regulation of Cop9 signalosome activity by the EF-hand Ca2+-binding protein tescalcin.
abstract: The Ca(2+)-binding protein tescalcin is known to be involved in hematopoietic cell differentiation; however, this mechanism is poorly understood. Here, we identify CSN4 (subunit 4 of the COP9 signalosome) as a novel binding partner of tescalcin. The COP9 signalosome (CSN) is a multiprotein complex that is essential for development in all eukaryotes. This interaction is selective, Ca(2+)-dependent and involves the PCI domain of CSN4 subunit. We then investigated tescalcin and CSN activity in human erythroleukemia HEL and promyelocytic leukemia K562 cells and find that phorbol 12-myristate 13-acetate (PMA)-induced differentiation, resulting in the upregulation of tescalcin, coincides with reduced deneddylation of cullin-1 (Cul1) and stabilization of p27(Kip1) - molecular events that are associated with CSN activity. The knockdown of tescalcin led to an increase in Cul1 deneddylation, expression of F-box protein Skp2 and the transcription factor c-Jun, whereas the levels of cell cycle regulators p27(Kip1) and p53 decreased. These effects are consistent with the hypothesis that tescalcin might play a role as a negative regulator of CSN activity towards Cul1 in the process of induced cell differentiation.
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA klevay@med.miami.edu VSlepak@med.miami.edu.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Levay
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL 33136, USA Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA klevay@med.miami.edu VSlepak@med.miami.edu.
authors.forename: Vladlen Z
authors.initials: VZ
authors.lastname: Slepak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D044842:Cullin Proteins / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C555813:COPS4 protein, human; D002135:Calcium-Binding Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D044786:S-Phase Kinase-Associated Proteins; C486009:TESC protein, human; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048031:JNK Mitogen-Activated Protein Kinases; D000075686:COP9 Signalosome Complex; D002118:Calcium
keywords: COP9 signalosome; Cell cycle; Cullin; Tescalcin; p27