FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas
ABSTRACT BCL6 is the product of a proto-oncogene implicated in the pathogenesis of human B-cell lymphomas. By binding specific DNA sequences, BCL6 controls the transcription of a variety of genes involved in B-cell development, differentiation and activation. BCL6 is overexpressed in the majority of patients with aggressive diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in adulthood, and transgenic mice constitutively expressing BCL6 in B cells develop DLBCLs similar to the human disease. In many DLBCL patients, BCL6 overexpression is achieved through translocation (~40%) or hypermutation of its promoter (~15%). However, many other DLBCLs overexpress BCL6 through an unknown mechanism. Here we show that BCL6 is targeted for ubiquitylation and proteasomal degradation by a SKP1–CUL1–F-box protein (SCF) ubiquitin ligase complex that contains the orphan F-box protein FBXO11 (refs 5, 6). The gene encoding FBXO11 was found to be deleted or mutated in multiple DLBCL cell lines, and this inactivation of FBXO11 correlated with increased levels and stability of BCL6. Similarly, FBXO11 was either deleted or mutated in primary DLBCLs. Notably, tumour-derived FBXO11 mutants displayed an impaired ability to induce BCL6 degradation. Reconstitution of FBXO11 expression in FBXO11-deleted DLBCL cells promoted BCL6 ubiquitylation and degradation, inhibited cell proliferation, and induced cell death. FBXO11-deleted DLBCL cells generated tumours in immunodeficient mice, and the tumorigenicity was suppressed by FBXO11 reconstitution. We reveal a molecular mechanism controlling BCL6 stability and propose that mutations and deletions in FBXO11 contribute to lymphomagenesis through BCL6 stabilization. The deletions/mutations found in DLBCLs are largely monoallelic, indicating that FBXO11 is a haplo-insufficient tumour suppressor gene.
- "Our results identify FBXO11 as an important miR-21 target gene. In addition, there was an inverse relationship between FBXO11 and BCL6 expression in various human cancer cell lines, and FBXO11 overexpression resulted in markedly lower BCL6 levels, which is consistent with the finding that FBXO11 directly mediates BCL6 degradation [Duan et al., 2012]. Although the role of BCL6 in lymphoma is fairly well defined [Parekh et al., 2007], these findings suggest that BCL6 may also play an important role in non-lymphoid cancers as well. "
Article: The Role of miR-21 in Cancer[Show abstract] [Hide abstract]
ABSTRACT: Preclinical Research MicroRNAs (miRNAs) are small endogenous noncoding RNAs that suppress gene expression at the post-transcriptional level. In the past decade, miRNAs have been extensively studied in a number of different human cancers. MiRNAs have been identified to act both as oncogenes and as tumor suppressors. In addition, miRNAs are associated with the intrinsic resistance of cancer to various forms of therapy, and they are implicated in both tumor progression and metastasis. The characterization of the specific alterations in the patterns of miRNA expression in cancer has great potential for identifying biomarkers for early cancer detection, as well as for potential therapeutic intervention in cancer treatment. In this chapter, we describe the ever-expanding role of miR-21 and its target genes in different cancers, and provide insight into how this oncogenic miRNA regulates cancer cell proliferation, migration, and apoptosis by suppressing the expression of tumor suppressors. Drug Dev Res, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.Drug Development Research 06/2015; DOI:10.1002/ddr.21257 · 0.77 Impact Factor
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- "TP53 responds to diverse cellular stresses by regulating the expression of specific target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair or metabolic changes (Dai and Gu 2010; Lane 1992). An example of cluster 1 protein is the F-box protein FBOX11, which interacts with the E3 ubiquitin–protein ligase complex that mediates ubiquitination and subsequent proteasomal degradation of target proteins involved in diverse biological process (Duan et al. 2012), which therefore can be predicted to be sensitive to zinc availability . Of the 20 top ZNBPs in cluster 3, twelve are involved in gene expression either directly, as transcription factors (tumor suppressor genes P53, P63, BCL6, SSH, PML, SMAD2, SMAD3, SMAD4, SMAD7), or indirectly, as regulators of the DNA dwelling or DNA repair processes (HDAC4, HDAC5, BRCA1). "
ABSTRACT: Zinc is an essential micronutrient playing fundamental roles in cellular metabolism. It acts mostly through binding a wide range of proteins, thus affecting a broad spectrum of biological processes, which include cell division, growth and differentiation. Full annotation of zinc-binding proteins showed them to represent about 10 % of the human proteome, with over 300 enzymes containing zinc ions within their catalytic domains. Also, hundreds of key regulatory proteins, including transcription factors, require zinc for their activity. In this study, the whole set of zinc-binding proteins together with their direct interactors was listed and defined as the zinc proteome (ZNP). We interrogated pathway analysis tools to identify the cellular processes that are predicted to be affected by zinc availability. Network and functional enrichment analyses highlighted biological processes potentially affected by deregulated zinc homeostasis. This computational approach was also tested on a real case study: The possible involvement of ZNP network proteins in Crohn's disease pathogenesis was assessed on genes transcriptionally regulated in the intestine of patients affected by this condition. The analysis produced a network of pathways likely to be influenced by zinc and associated with Crohn's disease. These results highlight a central role for zinc in the tissue remodeling process which occurs upon gut inflammation, pointing at novel disease pathways whose effect could be worsened by zinc dyshomeostasis and impaired zinc fluxes in specific damaged areas. Overall, our computational approach could provide novel insights into pathological conditions and could therefore be used to drive mechanistic research in under-investigated fields of research. An interactive version of the determined ZNP network is available at URL http://18.104.22.168/ZNnetwork/ .Genes & Nutrition 11/2014; 9(6):436. DOI:10.1007/s12263-014-0436-0 · 2.79 Impact Factor
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- "and MYC have been previously described in BL (Johnston and Carroll, 1992; Wilda et al., 2004) and changes in FBXO11 (Duan et al., 2012) and DDX3X (Wang et al., 2011) have been recently characterized in other B-cell malignancies, like diffuse large B-cell lymphomas (DLBCL), and chronic lymphocytic leukemia, respectively. Moreover , recent studies showed ID3 mutations to activate the PI3-kinase pathway in BLs (Love et al., 2012; Richter et al., 2012; Schmitz et al., 2012). "
ABSTRACT: Burkitt lymphoma (BL) is the most frequent B-cell lymphoma in childhood. Genetically, it is characterized by the presence of an IG-MYC translocation which is supposed to be an initiating but not sufficient event in Burkitt lymphomagenesis. In a recent whole-genome sequencing study of four cases, we showed that the gene encoding the ras homolog family member A (RHOA) is recurrently mutated in pediatric BL. Here, we analyzed RHOA by Sanger sequencing in a cohort of 101 pediatric B-cell lymphoma patients treated according to Non-Hodgkin's Lymphoma Berlin–Frankfurt–Münster (NHL-BFM) study protocols. Among the 78 BLs in this series, an additional five had RHOA mutations resulting in a total incidence of 7/82 (8.5%) with c.14G>A (p.R5Q) being present in three cases. Modeling the mutational effect suggests that most of them inactivate the RHOA protein. Thus, deregulation of RHOA by mutation is a recurrent event in Burkitt lymphomagenesis in children. © 2014 Wiley Periodicals, Inc.Genes Chromosomes and Cancer 11/2014; 53(11). DOI:10.1002/gcc.22202 · 4.04 Impact Factor