The role of the deubiquitinating enzyme CYLD and its substrate BCL-3 in solid tumors
type: CreativeWork
description: 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 express…
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 express…
author: Ahlqvist, Kristofer
language: eng
keywords: Clinical Medicine
date published: 2012
date modified: 2026-07-24T02:59:36Z
provider: University of Lund
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Molecular tumor Pathology