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

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

Biochimica et biophysica acta. Molecular cell research (2020-12-07)
Franco Andrés Pascucci, María Fátima Ladelfa, María Fernanda Toledo, Micaela Escalada, Melisa Suberbordes, Martín Monte
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Z-Leu-Leu-Leu-al, ≥90% (HPLC)
Sigma-Aldrich
Anti-HA antibody, Mouse monoclonal, clone HA-7, purified from hybridoma cell culture
Supelco
Cypermethrin solution, 100 μg/mL in acetonitrile, PESTANAL®, analytical standard