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(NF-kB / signal transduction / STAT3)
Abstract: BCL3 is a putative proto-oncogene deregulated in haematopoieitic and solid tumours. It has been suggested that its oncogenic effects could be mediated, at least in part, by inducing proliferation and inhibiting cell death. To provide more insight into the mediators of these effects, we used an unbiased approach to analyse the mRNA expression changes after knocking-down BCL3 using specific shRNAs. One hundred eighty genes were up-regulated and sixtynine genes were down-regulated after knocking down BCL3. Function analyses showed enrichment in genes associated with cellular growth and proliferation, cell death and gene expression. We found that STAT3, an important oncogene in human cancer, was the central node of one of the most significant networks. We validated STAT3 as a bona fide target of BCL3 by additional interference RNA and in silico analyses of previously reported lymphoma patients.
Abbreviations: IPA - Ingenuity Analysis Pathway, SDS-PAGE - sodium dodecyl sulphate-polyacrylamide gels, STAT3 - signal transducer and activator of transcription 3.
Introduction
NF-kB is a pleiotropic transcription factor that responds to cytokine signalling and cellular stress translocating to the nucleus and binding to a common DNA sequence motif, the kB box (Aggarwal, 2004). This factor is composed of several homo- or heterodimers of Rel-domain-containing proteins, which are kept inactive in the cytoplasm by a member of a family of anchorin-domain-containing proteins termed ?-?? proteins. After a stimulus, the inhibitory protein is phosphorylated, ubiquitinated and degraded, allowing the release of the NF-kB complex. The protein encoded by proto-oncogene BCL3 is atypical among the inhibitory proteins, since it is also able to act as transcriptional co-activator (Fujita et al., 1993). This protein, together with NFKBl, constitutes an alternative NF-?? pathway, variously called "non-canonical" (Cristofanon et al., 2009), "atypical" (Perkins, 2007) or "pathway 3" (Gilmore, 2006), in which no upstream receptor or activator is known. BCL3 was initially identified in a chromosome translocation from chronic lymphocytic leukaemia, although it has also been found over-expressed and/or activated in diverse solid tumours (Cogswell et al., 2000; Thornburg et al., 2003). Although not completely understood, the oncogenic potential of BCL3 could be derived from its effects in cell proliferation and death. It has been shown that this proto-oncogene, in conjunction with NFKB2 (p52), activates the...