MAGE-I proteins and cancer-pathways: A bidirectional relationship.

Data emerged from the last 20 years of basic research on tumor antigens positioned the type I MAGE (Melanoma Antigen GEnes - I or MAGE-I) family as cancer driver factors. MAGE-I gene expression is mainly restricted to normal reproductive tissues. However, abnormal re-expression in cancer unbalances the cell status towards enhanced oncogenic activity or reduced tumor suppression. Anomalous MAGE-I gene re-expression in cancer is attributed to altered epigenetic-mediated chromatin silencing. Still, emerging data indicate that MAGE-I can be regulated at protein level. Results from different laboratories suggest that after its anomalous re-expression, specific MAGE-I proteins can be regulated by well-known signaling pathways or key cellular processes that finally potentiate the cancer cell phenotype. Thus, MAGE-I proteins both regulate and are regulated by cancer-related pathways. Here, we present an updated review highlighting the recent findings on the regulation of MAGE-I by oncogenic pathways and the potential consequences in the tumor cell behavior.

Expression of the tumor-expressed protein MageB2 enhances rRNA transcription.

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.

MageC2 protein is upregulated by oncogenic activation of MAPK pathway and causes impairment of the p53 transactivation function.

Normal-to-tumor cell transition is accompanied by changes in gene expression and signal transduction that turns the balance toward cancer-cell phenotype, eluding by different mechanisms, the response of tumor-suppressor genes. Here, we observed that MageC2, a MAGE-I protein able to regulate the p53 tumor-suppressor, is accumulated upon MEK/ERK MAPK activation. Overexpression of H-RasV12 oncogene causes an increase in MageC2 protein that is prevented by pharmacologic inhibition of MEK. Similarly, decrease in MageC2 protein levels is shown in A375 melanoma cells (which harbor B-RafV600E oncogenic mutation) treated with MEK inhibitors. MageC2 protein levels decrease when p14ARF is expressed, causing an Mdm2-independent upregulation of p53 transactivation. However, MageC2 is refractory to p14ARF-driven downregulation when H-RasV12 is co-expressed. Using MageC2 knockout A375 cells generated by CRISPR/CAS9 technology, we demonstrated the relevance of MageC2 protein in reducing p53 transcriptional activity in cells containing hyperactive MEK/ERK signaling. Furthermore, gene expression analysis performed in cancer-genomic databases, supports the correlation of reduced p53 transcriptional activity and high MageC2 expression, in melanoma cells containing Ras or B-Raf driver mutations. Data presented here suggest that MageC2 can be a functional target of the oncogenic MEK/ERK pathway to regulate p53.