Oncotarget

Research Papers:

MXD1 localizes in the nucleolus, binds UBF and impairs rRNA synthesis

Maria del Carmen Lafita-Navarro, Rosa Blanco, Jorge Mata-Garrido, Judit Liaño-Pons, Olga Tapia, Lucía García-Gutiérrez, Eva García-Alegría, María T. Berciano, Miguel Lafarga and Javier León _

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Oncotarget. 2016; 7:69536-69548. https://doi.org/10.18632/oncotarget.11766

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Abstract

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: leonj@unican.es

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.


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