RESUMEN
An essential requirement for cells to sustain a high proliferating rate is to be paired with enhanced protein synthesis through the production of ribosomes. For this reason, part of the growth-factor signaling pathways, are devoted to activate ribosome biogenesis. Enhanced production of ribosomes is a hallmark in cancer cells, which is boosted by different mechanisms. Here we report that the nucleolar tumor-protein MageB2, whose expression is associated with cell proliferation, also participates in ribosome biogenesis. Studies carried out in both siRNA-mediated MageB2 silenced cells and CRISPR/CAS9-mediated MageB2 knockout (KO) cells showed that its expression is linked to rRNA transcription increase independently of the cell proliferation status. Mechanistically, MageB2 interacts with phospho-UBF, a protein which causes the recruitment of RNA Pol I pre-initiation complex required for rRNA transcription. In addition, cells expressing MageB2 displays enhanced phospho-UBF occupancy at the rDNA gene promoter. Proteomic studies performed in MageB2 KO cells revealed impairment in ribosomal protein (RPs) content. Functionally, enhancement in rRNA production in MageB2 expressing cells, was directly associated with an increased dynamic in protein synthesis. Altogether our results unveil a novel function for a tumor-expressed protein from the MAGE-I family. Findings reported here suggest that nucleolar MageB2 might play a role in enhancing ribosome biogenesis as part of its repertoire to support cancer cell proliferation.
Asunto(s)
Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Ribosomas/metabolismo , Antígenos de Neoplasias/fisiología , Línea Celular Tumoral , Nucléolo Celular/metabolismo , Proliferación Celular/genética , ADN Ribosómico/genética , ADN Ribosómico/metabolismo , Células HCT116 , Células HEK293 , Humanos , Proteínas de Neoplasias/fisiología , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , Regiones Promotoras Genéticas/genética , Biosíntesis de Proteínas , Procesamiento Proteico-Postraduccional , Proteómica , ARN Polimerasa I/metabolismo , ARN Ribosómico/biosíntesis , Ribosomas/genética , Transcripción Genética/genéticaRESUMEN
Since its discovery in 1991, the knowledge about the tumor specific melanoma antigen gene (MAGE-I) family has been continuously increasing. Initially, MAGE-I proteins were considered as selective targets for immunotherapy. More recently, emerging data obtained from different cellular mechanisms controlled by MAGE-I proteins suggest a key role in the regulation of important pathways linked to cell proliferation. This is in part due to the ability of some MAGE-I proteins to control the p53 tumor suppressor. In this review, we focus on the mechanisms proposed to explain how MAGE-I proteins affect p53 functions.