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MXD1 Localizes in the Nucleolus, Binds UBF and Impairs Rrna Synthesis

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MXD1 Localizes in the Nucleolus, Binds UBF and Impairs Rrna Synthesis www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 43 Research Paper MXD1 localizes in the nucleolus, binds UBF and impairs rRNA synthesis Maria del Carmen Lafita-Navarro1,3, Rosa Blanco1, Jorge Mata-Garrido2, Judit Liaño-Pons1, Olga Tapia2, Lucía García-Gutiérrez1, Eva García-Alegría1,4, María T. Berciano2, Miguel Lafarga2, Javier León1 1Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria, and Department of Molecular Biology, University of Cantabria, Santander, Spain 2Department of Anatomy and Cell Biology and Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), University of Cantabria-IDIVAL, Santander, Spain 3Present address: Department of Cell Biology, UT Southwestern Medical Center, Dallas, Texas, USA 4Present address: Stem Cell Hematopoiesis Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, United Kingdom Correspondence to: Javier León, email: [email protected] Keywords: MXD1, UBF, nucleolus, pre-rRNA, transcription regulation Received: June 20, 2016 Accepted: August 26, 2016 Published: August 31, 2016 ABSTRACT MXD1 is a protein that interacts with MAX, to form a repressive transcription factor. MXD1-MAX binds E-boxes. MXD1-MAX antagonizes the transcriptional activity of the MYC oncoprotein in most models. It has been reported that MYC overexpression leads to augmented RNA synthesis and ribosome biogenesis, which is a relevant activity in MYC-mediated tumorigenesis. Here we describe that MXD1, but not MYC or MNT, localizes to the nucleolus in a wide array of cell lines derived from different tissues (carcinoma, leukemia) as well as in embryonic stem cells. MXD1 also localizes in the nucleolus of primary tissue cells as neurons and Sertoli cells. The nucleolar localization of MXD1 was confirmed by co-localization with UBF. Co-immunoprecipitation experiments showed that MXD1 interacted with UBF and proximity ligase assays revealed that this interaction takes place in the nucleolus. Furthermore, chromatin immunoprecipitation assays showed that MXD1 was bound in the transcribed rDNA chromatin, where it co-localizes with UBF, but also in the ribosomal intergenic regions. The MXD1 involvement in rRNA synthesis was also suggested by the nucleolar segregation upon rRNA synthesis inhibition by actinomycin D. Silencing of MXD1 with siRNAs resulted in increased synthesis of pre-rRNA while enforced MXD1 expression reduces it. The results suggest a new role for MXD1, which is the control of ribosome biogenesis. This new MXD1 function would be important to curb MYC activity in tumor cells. INTRODUCTION MXD1 acts as antagonist of MYC transcriptional activity [5–7]. Conversely to MYC, MXD1 is readily expressed MXD1 (also known as MAD1) is a transcription in resting and differentiated cells [6, 8, 9]. Moreover, factor belonging to the MXD family of proteins [1]. MXD1 inhibits cell proliferation and antagonize MYC The MXD family (composed of MXD1, MXI1/MXD2, transforming activity [10–12]. MXD3, MXD4 and MNT) is part of the MYC-MAX- The nucleolus is the nuclear factory for rRNA MXD network of transcription factors. These factors synthesis, posttranscriptional processing of pre-rRNA contain the b-HLH-LZ domain by which they bind to and assembly of preribosomal particles. It is organized E-boxes in the promoter of their target genes to regulate around clusters of tandem repeats of RNA genes (rDNA) their transcription [2–4].Whereas MYC-MAX activates that encode the rRNAs 28S, 18S and 5.8S. The nucleolar transcription, MXD1-MAX represses transcription structure, composed of fibrillar centers (FCs), dense forming complexes with histone deacetylases. Therefore, fibrillar component (DFC) and granular component www.impactjournals.com/oncotarget 69536 Oncotarget (GC), reflects the sequential steps of ribosome biogenesis of neurons was demonstrated by co-localization with [13–15]. The FC concentrates components of the UBF (Figure 1A, lower panel). Moreover, immunogold transcription machinery, such as RNA polymerase I and electron microscopy confirmed the localization of UBF (Upstream Binding Factor), an essential transcription MXD1 in FCs and associated DFC of the neuronal factor of ribosomal genes [16]. The DFC partially nucleolus (Figure 2B). To further confirm this subnuclear surrounds FCs and contains transcriptionally active distribution, we transfected HeLa cells with a GFP-MXD1 ribosomal genes and numerous RNA-binding proteins. construct. As controls, we also transfected a GFP-MNT RNA pol I transcription takes place in the FCs and in and GFP constructs. Following 24 h of transfection, the the DFC, with further posttranscriptional processing of transfected GFP-MXD1 protein was diffusely distributed pre-rRNA occurring within the DFC to give rise to the in the nucleoplasm, but concentrated in the nucleolus mature rRNAs [17, 18]. The GC is where the 40S and 60S (Figure 3A). The nucleolar localization of exogenous ribosome subunits are assembled [19, 20]. GFP-MXD1 was confirmed by immunofluorescence with MXD1 was described as nuclear in fibroblasts [1] the anti-UBF antibody, showing the co-localization of and quiescent keratinocytes [21], but the subcellular GFP and UBF signals (Figure 3B). localization of endogenous MXD1 is unknown for most We next studied whether the nucleolar distribution cell types. Here we report that MXD1 localizes in the of MXD1 was extensible to MYC and another member cell nucleolus and describe an interaction of MXD1 with of the MXD family as MNT. In sharp contrast to MXD1, UBF. In addition, we show that MXD1 binds to rDNA and both MYC and MNT were present in the nucleoplasm regulates rDNA transcription. but excluded from the UBF-immunolabeled nucleoli in most cells (Figure 4). Fluorescence intensity line profiles RESULTS confirmed the absence of MYC and MNT in the nucleolus (Supplementary Figure S2). Moreover, overexpressed MNT MXD1 localization in the nucleolus did not accumulate in the nucleolus, as shown in HeLa cells transfected with a GFP-MNT construct (Figure 3A). We performed immunofluorescence studies in The co-localization of MXD1 and UBF in the FCs proliferating embryonic stem cells HS181, mesenchymal opened the possibility that MXD1 might be regulating stem cells MSC-3H, myeloid leukemia K562 cells, rDNA transcription. To test this, we treated HS181 and embryonic kidney HEK293T cells, and cervical cancer MSC-3H cells with actinomycin D at low concentration HeLa cells. Although it is reported that MXD1 is mostly (50 ng/ml for 1 h), and performed co-immunostaining for expressed in quiescent cells or differentiated cells, MXD1 and UBF. Under these conditions, actinomycin we found low but detectable MXD1 protein levels in D inhibits RNA pol I but not RNA pol II and RNA proliferating cells of the above cell lines (Figure 1A), pol III [24, 25]. We also treated rats systemically although serum deprivation resulted in increased MXD1 with actinomycin (300 µg/kg for 3 h) and analysed expression, as described [22] (Figure 1A). We chose the nucleolar reorganization in sensory neurons from some of these cell lines with higher MXD1 expression to trigeminal ganglia. Interestingly, we found that RNA study its subcellular localization. As shown in Figure 1B, pol I inhibition interfered with the nucleolar targeting MXD1 was localized in the nucleus in all cell lines but, of MXD1 in all cases, as a MXD1-free nucleolar area surprisingly, it was also concentrated in the nucleolus in appeared after treatment with actinomycin D, meanwhile a relevant proportion of cells (70% to 100% depending the nucleoplasmic signal of MXD1 remained unchanged on the cell line). The nucleolar distribution of MXD1 was (Figure 5). In MSC-3H cells and sensory neurons, MXD1 confirmed by its co-localization with UBF (Figure 1B), was segregated at the nucleolar periphery, forming typical a nucleolar marker of FCs [13, 23]. The nucleolar perinucleolar caps or rings in confocal images (Figure 5) localization for MXD1 is so far unreported and we set [26]. This effect was associated with disruption of FCs out to confirm this. Analysis of the fluorescence intensity and peripheral segregation of the UBF, suggesting that profiles of UBF and MXD1 in cell lines and neurons MXD1 localization in FCs correlates with ongoing rRNA demonstrated this co-localization (Supplementary synthesis and raising a possible role of this transcription Figure S1). We also asked if the subnuclear localization factor in the regulation of rDNA transcription. of MXD1 observed in cells in culture also occurred in primary tissue cells. We analysed by immunofluorescence Interaction between MXD1 and UBF Sertoli and germinal cells from rat seminiferous tube and rat sensory ganglion neurons. MXD1 was concentrated As UBF and MXD1 co-localized in the FCs of in the nucleolus, with a weaker nucleoplasmic signal, nucleolus, we asked whether MXD1 and UBF interacted in post-mitotic Sertoli cells and neurons (Figure 2A). in the nucleolus. We first performed immunoprecipitation The nucleolar localization of MXD1 was confirmed assays in HeLa cells. The cells were deprived from serum in preparations co-stained with propidium iodide for 48 h to augment MXD1 expression and the lysates (Figure 2A), and its preferential concentration in FCs were immunoprecipitated with anti-UBF antibodies. www.impactjournals.com/oncotarget 69537 Oncotarget Figure 1: Endogenous MXD1 localizes in the nucleolus. (A) MXD1 protein expression in growing cells from different cell lines used in this work. MXD1 levels
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