| 1. |
- Ahlqvist, Kristofer, et al.
(författare)
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Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.
- 2013
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 32:12, s. 1601-1608
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Tidskriftsartikel (refereegranskat)abstract
- B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.Oncogene advance online publication, 14 May 2012; doi:10.1038/onc.2012.175.
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| 2. |
- Ahlqvist, Kristofer
(författare)
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The role of the deubiquitinating enzyme CYLD and its substrate BCL-3 in solid tumors
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The tumor suppressor CYLD and the proto-oncogene BCL-3 are known to be deregulated in various cancer types. The molecular background of how these genes participate in carcinogenesis is not fully understood. CYLD is a deubiquitinating enzyme known to specifically target lysine 63 linked ubiquitin chains, which can negatively regulate the BCL-3, NF-κB and JNK signaling pathways, leading to a decrease of cell survival or proliferation. BCL-3 is an alternative IκB family member that is needed for activation (or repression) of target genes by homodimeric p50 and p52. The aim of this thesis was to further investigate the molecular mechanisms behind CYLD and BCL-3 regulation and how they might contribute to carcinogenesis. In particular, the role of BCL-3 in prostate cancer (PCa), and the role of CYLD in hepatocellular carcinoma (HCC) were studied. In PCa we found up-regulation of BCL-3 in human prostate cancers with abundant infiltration of inflammatory cells. Using PCa cell lines we found that interleukin-6 (IL-6) could activate STAT3 mediated up-regulation of BCL-3, which in turn could elevate Id-1 and Id-2 expression. Knockdown of BCL-3 increased the sensitivity for anticancer drug-induced apoptosis. PCa cells with reduced BCL-3 levels that were subcutaneously injected into NUDE mice formed smaller tumors due to a higher percentage of apoptotic cells. In other tissues Bcl-3 has been shown to regulate proliferation through expression of its target gene CYCLIN D1, a process that is negatively regulated by CYLD. We found that CYLD knockout MEF cells have significantly increased proliferation rates and increased levels of CYCLIND1 in a serum dependent manner when compared with wild type MEF cells. The reduced proliferation in wild type cells was mediated through up-regulation of CYLD by transcription factor serum response factor (SRF) in a p38 mitogen-activated protein kinase (p38MAPK) dependent manner. Knockdown of SRF by siRNA or inhibition of p38MAPK reduced the expression of CYLD and increased cell proliferation rate. These results suggest that SRF is a positive regulator of CYLD expression, which in turn reduces the mitogenic activation of wild type MEF cells. For further investigation of the molecular mechanisms of CYLD in cancer we performed a tissue microarray, comparing benign liver tissue with HCC. We found that CYLD is significantly down-regulated in human (HCC) and that CYLD expression was inversely correlated with the expression of proliferation marker Ki67. In vivo experiments showed that CYLD deficient mice were more susceptible to the chemical carcinogen DEN-induced HCC. Furthermore, HCC isolated from CYLD knockout mice had elevated cell proliferation compared to wild type mice. This effect was mediated via TRAF-2 ubiquitination, JNK activation and c-MYC expression. In correlation to this result, transient transfection of CYLD into a HCC cell line restricted cell proliferation and reduced the activation of JNK. Together these results suggest that CYLD down-regulation is a risk factor for development and progression of HCC mediated through activation of JNK1
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| 3. |
- Liang, Gang, et al.
(författare)
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Serum Response Factor Controls CYLD Expression via MAPK Signaling Pathway.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:5
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Tidskriftsartikel (refereegranskat)abstract
- Tumor suppressor gene CYLD is a deubiquitinating enzyme which negatively regulates various signaling pathways by removing the lysine 63-linked polyubiquitin chains from several specific substrates. Loss of CYLD in different types of tumors leads to either cell survival or proliferation. In this study we demonstrate that lack of CYLD expression in CYLD-/- MEFs increases proliferation rate of these cells compared to CYLD+/+ in a serum concentration dependent manner without affecting cell survival. The reduced proliferation rate in CYLD+/+ in the presence of serum was due to the binding of serum response factor (SRF) to the serum response element identified in the CYLD promoter for the up-regulation of CYLD levels. The serum regulated recruitment of SRF to the CYLD promoter was dependent on p38 mitogen-activated protein kinase (MAPK) activity. Elimination of SRF by siRNA or inhibition of p38 MAPK reduced the expression level of CYLD and increased cell proliferation. These results show that SRF acts as a positive regulator of CYLD expression, which in turn reduces the mitogenic activation of serum for aberrant proliferation of MEF cells.
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| 4. |
- Rajeswara, Pannem Rao, et al.
(författare)
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CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma.
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:2, s. 461-468
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Tidskriftsartikel (refereegranskat)abstract
- Post-translational modification of different proteins via direct ubiquitin attachment is vital for mediating various cellular processes. CYLD, a deubiquitination enzyme, is able to cleave the polyubiquitin chains from the substrate, and to regulate different signaling pathways. Loss, or reduced expression, of CYLD is observed in different types of human cancer, such as hepatocellular carcinoma (HCC). However, the molecular mechanism by which CYLD affects cancerogenesis has to date not been unveiled. The aim of the present study was to examine how CYLD regulates cellular functions and signaling pathways during hepatocancerogenesis. We found that mice lacking CYLD were highly susceptible to chemically induced liver cancer. The mechanism behind proved to be an elevated proliferation rate of hepatocytes, owing to sustained JNK1-mediated signaling via ubiquitination of TRAF2 and expression of c-MYC. Overexpression of wild type CYLD in an HCC cell lines prevented cell proliferation, without affecting apoptosis, adhesion, and migration. A combined immunohistochemical and tissue microarray analysis of 81 human HCC tissues revealed that CYLD expression is negatively correlated with expression of proliferation marker Ki-67 and c-MYC. To conclude, we found that downregulation of CYLD induces tumor cell proliferation, consequently contributing to the aggressive growth of HCC. Our findings suggest that CYLD holds potential to serve as a marker for HCC progression, and its link to c-MYC via JNK1 may provide the foundation for new therapeutic strategies for HCC-patients.
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