Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome

Uhle, Stefan; Medalia, Ohad; Waldron, Richard T.; Dumdey, R; Henklein, Peter; Bech‐Otschir, Dawadschargal; Huang, Xiaohua; Berse, Matthias; Sperling, Joseph; Schade, Rüdiger; Dubiel, Wolfgang

doi:10.1093/emboj/cdg127

Cited by 192 publications

(211 citation statements)

References 43 publications

(69 reference statements)

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“…66 In this work, we also observed that DRB induced a marked decrease of cJun protein level, both in normoxia and in hypoxia (data not shown). Since HIF-1 and AP-1 are known to cooperate to upregulated the expression of several genes in hypoxia, [67][68][69] degradation of c-Jun by DRB may partly explain the decreased VEGF expression in hypoxia.…”

Section: Discussionsupporting

confidence: 56%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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Section: Discussionsupporting

confidence: 56%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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“…Aliquots were subjected to SDS-PAGE and Western blotting. The following antibodies were used in this study: anti-CSN1, anti-CSN4, anti-CSN6 and anti-CSN8 antibodies (Biomol), anti-CSN2, anti-CSN3 and anti-CSN7 antibodies [29,30], monoclonal anti-CSN5 antibody (supplied by B. Christy), anti-ubiquitin antibody (FK2, Biomol), anti-USP15 antibody [31], anti-Rbx1 antibody (Rockland), anti-Nedd8 antibody (a gift from C.…”

Section: Cell Culture and Materialsmentioning

confidence: 99%

“…Kinase activity was 6 detected by addition of 0.5 µg recombinant c-Jun and [γ-32 P]-ATP to the pre-incubated CSN complex. Phosphorylation of c-Jun was determined as described previously [30].…”

Section: Csn Activity Assaysmentioning

confidence: 99%

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The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis

et al. 2007

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In concert with the ubiquitin (Ub) proteasome system (UPS) the COP9 signalosome (CSN) controls the stability of cellular regulators. The CSN interacts with cullin-RING Ub ligases (CRLs) consisting of a specific cullin, a RING protein as Rbx1 and substrate recognition proteins. The Ub-like protein Nedd8 is covalently linked to cullins and removed by the CSN-mediated deneddylation. Cycles of neddylation and deneddylation regulate CRLs. Apoptotic stimuli cause caspase-dependent modifications of the UPS.

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“…CSN has an intrinsic isopeptidase activity that deconjugates the ubiquitin-like protein Nedd8/Rub1 from cullin ubiquitin ligases (deneddylation) (Cope and Deshaies 2003). In addition, the complex can associate with protein kinases such as protein kinase CK2 (CK2, formerly casein kinase II), protein kinase D (PKD), and inositol 1,3,4-triphosphate 5/6-kinase (5/6-kinase), which have been shown to phosphorylate c-Jun (Wilson et al, 2001;Uhle et al, 2003). One of CSN subunits, CSN5, also known as Jab1 (c-Jun activation domain binding protein 1), has been identified as a transcription co-activator that enhances transcription activity of c-Jun (Claret et al, 1996) and Myc (Adler et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1

et al. 2011

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CSN1 is a component of the COP9 signalosome (CSN), a conserved protein complex with pleiotropic functions in many organs and cell types. CSN regulates ubiquitinproteasome dependent protein degradation via the deneddylation and the associated deubiquitination activities. In addition, CSN associates with protein kinases and modulates cell signaling, particularly the activator protein 1 (AP-1) pathway. We have shown previously that CSN1 suppresses AP-1 transcription activity and inhibits ultraviolet (UV) and serum activation of c-fos expression. Here we show that CSN1 can inhibit phosphorylation of proto-oncogene c-Jun product and repress c-Jun dependent transcription. Further, CSN1 dramatically downregulates ectopic expression of c-Jun N-terminal kinase 1 (JNK1) in cultured cells. The decline in JNK1 is not caused by excessive proteolysis or by 3′ UTR-dependent mRNA instability, but by CSN1-dependent repression of one or multiple steps in transcriptional and posttranscriptional mechanisms. Thus, in contrast to CSN5/ Jab1, which promotes AP-1 activity, CSN1 displays a negative effect on the AP-1 pathway. Finally, we discuss about the dynamic equilibrium of the CSN complexes in regulation of the AP-1 pathway.

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Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome

Cited by 192 publications

References 43 publications

Role for casein kinase 2 in the regulation of HIF‐1 activity

Role for casein kinase 2 in the regulation of HIF‐1 activity

The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis

CSN1 inhibits c-Jun phosphorylation and down-regulates ectopic expression of JNK1

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