Regulation of the anaphase-promoting complex by the COP9 signalosome

Core Unit Chip Application, Institute of Human Genetics and Anthropology, Jena University Hospital, Jena, Germany.
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 08/2009; 8(13):2041-9. DOI: 10.4161/cc.8.13.8850
Source: PubMed


The COP9 complex (signalosome) is a known regulator of the proteasome/ubiquitin pathway. Furthermore it regulates the activity of the cullin-RING ligase (CRL) families of ubiquitin E3-complexes. Besides the CRL family, the anaphase-promoting complex (APC/C) is a major regulator of the cell cycle. To investigate a possible connection between both complexes we assessed interacting partners of COP9 using an in vivo protein-protein interaction assay. Hereby, we were able to show for the first time that CSN2, a subunit of the COP9 signalosome, interacts physically with APC/C. Furthermore, we detected a functional influence of the COP9 complex regarding the stability of several targets of the APC/C. Consistent with these data we showed a genetic instability of cells overexpressing CSN2.

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    • "Noteworthy, Set8 degradation is mediated by two other ligases: CRL1 Skp2 and anaphase promoting complex/cyclosome (APC/ C) Cdh1 [114]. The latter has not yet been shown to be modified by Nedd8 but it is also affected by the CSN [115]. Notably, CRL4A CDT2 also targets p21 for degradation [116] [117]. "
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    ABSTRACT: The COP9 signalosome (CSN) is a platform for protein communication in eukaryotic cells. It has an intrinsic metalloprotease that removes the ubiquitin (Ub)-like protein Nedd8 from cullins. CSN-mediated deneddylation regulates culling-RING Ub ligases (CRLs) and controls ubiquitination of proteins involved in DNA damage response (DDR). CSN forms complexes with CRLs containing cullin 4 (CRL4s) which act on chromatin playing crucial roles in DNA repair, checkpoint control and chromatin remodeling. Furthermore, via associated kinases the CSN controls the stability of DDR effectors such as p53 and p27 and thereby the DDR outcome. DDR is a protection against cancer and deregulation of CSN function causes cancer making it an attractive pharmacological target. Here we review current knowledge on CSN function in DDR.
    FEBS letters 04/2011; 585(18):2845-52. DOI:10.1016/j.febslet.2011.04.027 · 3.17 Impact Factor
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    • "Therefore, it appears that in U2OS and HeLa cells, celltype-specific mechanisms might be in place that restrict APC/C activity. Possibly, deubiquitinases like USP28 (Zhang et al., 2006; Bassermann et al., 2008), lack of APC/C-specific E2 enzymes, weakened APC/C-proteasome interaction (Kob et al., 2009), a defect in the downregulation of APC/C substrate mRNAs and/or the moderate strength of premature APC/C induction (Supplementary Figure S6) could be responsible for the low effectiveness of APC/C activity in these cells. "
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    ABSTRACT: The long-term cellular response to DNA damage is controlled by the tumor suppressor p53. It results in cell-cycle arrest followed by DNA repair and, depending on the degree of damage inflicted, premature senescence or apoptotic cell death. Here we show that in normal diploid fibroblasts the ubiquitin ligase anaphase-promoting complex or cyclosome (APC/C)-Cdh1 becomes prematurely activated in G2 as part of the sustained long-term but not the rapid short-term response to genotoxic stress and results in the degradation of numerous APC/C substrates. Using HCT116 somatic knockout cells we show that mechanistically premature APC/C activation depends on p53 and its transcriptional target p21 that mediates the signal through downregulation of the APC/C inhibitor Emi1. Cdc14B is dispensable in this setting but might function redundantly. Our data suggest an unexpected role for the APC/C in executing a part of the p53-dependent DNA damage response that leads to premature senescence.
    Oncogene 04/2010; 29(24):3477-89. DOI:10.1038/onc.2010.99 · 8.46 Impact Factor
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    • "N mutants ( defects in CSN3 , 4 or 5ab ) are delayed in G2 phase progression , which accompanied induc - tion of the DNA damage - response pathway ( Dohmann et al . 2008 ) . Recent papers reported that the CSN ( CSN2 subunit ) physically interacts with the com - ponents of the anaphase - promoting complex ⁄ cyclosome ( APC ⁄ C , APC1 , 4 and 6 ) ( Kob et al . 2009 ) , presenting a direct connection between the CSN and G2 ⁄ M phase progression . Because the APC ⁄ C component is known to control the endocycle ( Zielke et al . 2008 ) , the CSN may regulate endorepli - cation as well . Thus , the CSN controls multiple steps in the cell cycle progression , dependent on tissue - specificity and subunit"
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    ABSTRACT: The COP9 signalosome (CSN) complex is highly conserved from yeast to human. Although the plant CSN was first identified as a negative regulator of photomorphogenesis, the mammalian CSN is linked to different biological responses such as checkpoint control, signal transduction, development and the cell cycle. Frequent over-expression of the CSN subunit in a variety of human cancers suggests its involvement in cell transformation and tumorigenesis. The best-known biochemical function associated with the CSN is the control of protein stability via the ubiquitin-proteasome system through regulation of cullin-RING-E3 ubiquitin ligase activity by deneddylation, by controlling the activity of COP1 E3 ligase, or by counteracting ubiquitin-mediated degradation through a CSN-associated deubiquitinating enzyme. In addition to affecting the stability of transcription factors, the CSN may regulate gene transcription by directly associating with chromatin. This review summarizes recent findings and discusses the physiological role and the cellular function of the mammalian CSN in terms of the regulation of cell proliferation.
    Genes to Cells 11/2009; 14(11):1209-25. DOI:10.1111/j.1365-2443.2009.01349.x · 2.81 Impact Factor
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