| 1. |
- An, Jiabin, et al.
(författare)
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Inactivation of the CYLD Deubiquitinase by HPV E6 Mediates Hypoxia-Induced NF-kappa B Activation
- 2008
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 14:5, s. 394-407
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Tidskriftsartikel (refereegranskat)abstract
- The biochemical mechanisms that underlie hypoxia-induced NF-kappa B activity have remained largely undefined. Here, we find that prolonged hypoxia-induced NF-kappa B activation is restricted to cancer cell lines infected with high-risk human papillomavirus (HPV) serotypes. The HPV-encoded E6 protein is necessary and sufficient for prolonged hypoxia-induced NF-kappa B activation in these systems. The molecular target of E6 in the NF-kappa B pathway is the CYLD lysine 63 (K63) deubiquitinase, a negative regulator of the NF-kappa B pathway. Specifically, hypoxia stimulates E6-mediated ubiquitination and proteasomal degradation of CYLD. Given the established role of NF-kappa B in human carcinogenesis, these findings provide a potential molecular/viral link between hypoxia and the adverse clinical outcomes observed in HPV-associated malignancies.
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| 2. |
- Bengtsson, Astrid, et al.
(författare)
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Leukotriene D(4) induces AP-1 but not NFkappaB signaling in intestinal epithelial cells.
- 2008
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Ingår i: Prostaglandins & other Lipid Mediators. - : Elsevier BV. - 1098-8823. ; 85:3-4, s. 100-106
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Tidskriftsartikel (refereegranskat)abstract
- We have previously shown that leukotriene D(4) (LTD(4)), a known pro-inflammatory mediator, induces increased survival and proliferation of intestinal epithelial cells. In this study we examined whether LTD(4) functions via activation of the transcription factors NFkappaB and AP-1, which are potent inducers of mitogenesis. We found that the NFkappaB inhibitory protein IkappaBalpha was not degraded upon LTD(4) stimulation. Furthermore, nuclear translocation of the classical p65 or alternative p52 subunits of NFkappaB was not observed. Accordingly, LTD(4) stimulation failed to induce NFkappaB transcriptional activity. Instead we found that LTD(4) induced phosphorylation of c-Jun-N-terminal kinase (JNK) and transcriptional activity of AP-1, which could be reduced by a JNK inhibitor. Moreover, LTD(4) induced cell proliferation, and this effect was also blocked upon addition of a JNK inhibitor. Our findings show for the first time that JNK/AP-1 but not NFkappaB is a downstream target of LTD(4) in intestinal epithelial cells, suggesting that AP-1 is an important mediator of LTD(4)-induced mitogenic effects.
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| 3. |
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| 4. |
- Broom, Oliver, et al.
(författare)
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CD47 regulates collagen I-induced cyclooxygenase-2 expression and intestinal epithelial cell migration.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:7, s. e6371-
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Tidskriftsartikel (refereegranskat)abstract
- Increased epithelial cell expression of the cyclooxygenase-2 (COX-2) enzyme is a characteristic event of both inflammatory bowel disease and colon cancer. We here report the novel findings that collagen I-induced de novo synthesis of COX-2 in intestinal epithelial cells is inhibited by pertussis toxin (PTX) and by an inhibitory peptide selective for the heterotrimeric G alpha(i3)-protein. These findings could be explained by a regulatory involvement of the G-protein-dependent integrin-associated protein CD47. In support of this notion, we observed a collagen I-induced association between CD47 and alpha2 integrins. This association was reduced by a blocking anti-CD47 antibody but not by PTX or a control anti-beta2 antibody. Furthermore, a blocking antibody against CD47, dominant negative CD47 or specific siRNA knock down of CD47, significantly reduced collagen I-induced COX-2 expression. COX-2 has previously been shown to regulate intestinal epithelial cell adhesion and migration. Morphological analysis of intestinal cells adhering to collagen I revealed a co-localisation of CD47 and alpha2 integrins to non-apoptotic membrane blebs enriched in Rho A and F-actin. The blocking CD47 antibody, PTX and a selective COX-2 inhibitor, dramatically inhibited the formation of these blebs. In accordance, migration of these cells on a collagen I-coated surface or through a collagen I gel were significantly reduced by the CD47 blocking antibody, siRNA knock down of CD47 and the COX-2 inhibitor NS-398. In conclusion, we present novel data that identifies the G-protein-dependent CD47 protein as a key regulator of collagen I-induced COX-2 expression and a promoter of intestinal epithelial cell migration.
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| 5. |
- Hellerbrand, Claus, et al.
(författare)
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Reduced expression of CYLD in human colon and hepatocellular carcinomas
- 2007
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 28:1, s. 21-27
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Tidskriftsartikel (refereegranskat)abstract
- CYLD was originally identified as a tumor suppressor that is mutated in familial cylindromatosis. Recent studies suggested a role for CYLD in nuclear factor-kappaB (NF-kappaB) regulation. NF-kappaB activation has been connected with multiple aspects of oncogenesis but the underlying molecular mechanisms of persistent NF-kappaB activation in tumors remain largely unknown. Thus, we evaluated CYLD transcription in different colon and hepatocellular carcinoma cell lines and tissue samples, respectively. CYLD was downregulated or lost in all tumor cell lines investigated as compared with primary human colonic epithelial cells and hepatocytes, respectively. Further, quantitative PCR analysis revealed reduced CYLD mRNA expression in most tumor samples compared with non-tumorous tissue. Analysis on protein level confirmed these findings. Functional assays with CYLD transfected cell lines revealed that CYLD expression decreased NF-kappaB activity. Thus, functional relevant loss of CYLD expression may contribute to tumor development and progression, and may provide a new target for therapeutic strategies.
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| 6. |
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| 7. |
- Hovelmeyer, Nadine, et al.
(författare)
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Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD
- 2007
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 204:11, s. 2615-2627
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Tidskriftsartikel (refereegranskat)abstract
- B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-kappaB (NF-kappaB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLD(ex7/8) mice), which is a deubiquitinating enzyme that is integral to NF-kappaB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves exhibit prolonged survival and manifest a variety of signaling disarrangements that do not occur in mice with a complete deletion of CYLD. Although both the full-length and the mutant CYLD are able to interact with Bcl-3, a predominant nuclear accumulation of Bcl-3 occurs in the CYLD mutant B cells. More dramatic, however, is the accumulation of the NF-kappaB proteins p100 and RelB in CYLD(ex7/8) B cells, which, presumably in combination with nuclear Bcl-3, results in increased levels of Bcl-2 expression. These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.
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| 8. |
- Massoumi, Ramin, et al.
(författare)
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Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling
- 2006
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 125:4, s. 665-677
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the CYLD gene cause tumors of hair-follicle keratinocytes. The CYLD gene encodes a deubiquitinase that removes lysine 63-linked ubiquitin chains from TRAF2 and inhibits p65/p50 NF-kappaB activation. Here we show that mice lacking Cyld are highly susceptible to chemically induced skin tumors. Cyld-/- tumors and keratinocytes treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) or UV light are hyperproliferative and have elevated cyclin D1 levels. The cyclin D1 elevation is caused not by increased p65/p50 action but rather by increased nuclear activity of Bcl-3-associated NF-kappaB p50 and p52. In Cyld+/+ keratinocytes, TPA or UV light triggers the translocation of Cyld from the cytoplasm to the perinuclear region, where Cyld binds and deubiquitinates Bcl-3, thereby preventing nuclear accumulation of Bcl-3 and p50/Bcl-3- or p52/Bcl-3-dependent proliferation. These data indicate that, depending on the external signals, Cyld can negatively regulate different NF-kappaB pathways; inactivation of TRAF2 controls survival and inflammation, while inhibition of Bcl-3 controls proliferation and tumor growth.
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| 9. |
- Massoumi, Ramin, et al.
(författare)
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Cylindroma as tumor of hair follicle origin
- 2006
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 1523-1747 .- 0022-202X. ; 126:5, s. 1182-1184
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Massoumi, Ramin, et al.
(författare)
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Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control
- 2007
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Ingår i: BioEssays. - : Wiley. - 0265-9247 .- 1521-1878. ; 29:12, s. 1203-1214
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Forskningsöversikt (refereegranskat)abstract
- Analysing cylindromatosis and the associated defects in the CYLD gene is providing novel insights into the molecular principles of epithelial growth control and carcinogenesis in, and beyond, the skin. In this review, we summarize the histopathology and histogenesis of cylindromas, and the available genetic information on patients with these skin appendage tumors. Focusing on recent data concerning the normal functions and signaling interactions of the CYLD gene product, we explain how CYLD interferes with TNF-alpha or TLR-mediated signaling as well as with JNK or NF-kappa B-dependent p65/50 signaling to limit inflammation. In addition, we delineate how CYLD interferes with activation of the proto-oncogene BCl3 and with cyclin D1 expression to limit tumorigenesis, and chart how tumor growth-promoting agents or UV light and inflammatory mediators can activate CYLD. We argue that these recent insights into CYLD function and cylindroma pathogenesis may lead to the development of novel molecular strategies for cancer prevention and treatment.
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