The oncogene PDRG1 is an interaction target of methionine adenosyltransferases
Entidad
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto de Investigación Sanitaria del Hospital Universitario de La Paz (IdiPAZ)Editor
Public Library of ScienceFecha de edición
2016-08-01Cita
10.1371/journal.pone.0161672
PLoS ONE 11.8 (2016): e0161672
ISSN
1932-6203DOI
10.1371/journal.pone.0161672Financiado por
This work was supported by grants of the Ministerio de Economía y Competitividad (BFU2005-00050, BFU2008-00666, BFU2009-08977), and the Instituto de Salud Carlos III Carlos III (RCMN C03/08 and PI05/0563)Proyecto
Gobierno de España. BFU2005-00050; Gobierno de España. BFU2008-00666; Gobierno de España. BFU2009-08977; Gobierno de España. RCMN C03/08; Gobierno de España. PI05/0563Versión del editor
https://doi.org/10.1371/journal.pone.0161672Materias
Methionine; Adenosyltransferases; Interactions; PDRG1; Target; MedicinaDerechos
© 2016 Pérez et al.Resumen
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high V max (MAT III) isoenzymes, whereas the low V max (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases.
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Google Scholar:Pérez, Claudia
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Pérez-Zúñiga, Francisco J.
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Garrido, Francisco
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Reytor, Edel
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Portillo Pérez, Francisco
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