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

FRANCO A PASCUCCI, PHD; MARIA F LADELFA, PHD; MARIA F TOLEDO, PHD; MICAELA ESCALADA; MELISA SUBERBORDES; MARTIN MONTE

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2020

0167-4889

Normal-to-tumor cell transition is accompanied by changes in gene expression andsignal transduction that turns the balance toward cancer-cell phenotype, eluding bydifferent mechanisms, the response of tumor-suppressor genes. Here, we observedthat MageC2, a MAGE-I protein able to regulate the p53 tumor-suppressor, isaccumulated upon MEK/ERK MAPK activation. Overexpression of H-RasV12oncogene causes an increase in MageC2 protein that is prevented by pharmacologicinhibition of MEK. Similarly, decrease in MageC2 protein levels is shown in A375melanoma cells (which harbor B-RafV600E oncogenic mutation) treated with MEKinhibitors. MageC2 protein levels decrease when p14ARF is expressed, causing anMdm2-independent upregulation of p53 transactivation. However, MageC2 is refractoryto p14ARF-driven downregulation when H-RasV12 is co-expressed. Using MageC2knockout A375 cells generated by CRISPR/CAS9 technology, we demonstrated therelevance of MageC2 protein in reducing p53 transcriptional activity in cells containinghyperactive MEK/ERK signaling. Furthermore, gene expression analysis performed incancer-genomic databases, supports the correlation of reduced p53 transcriptionalactivity and high MageC2 expression, in melanoma cells containing Ras or B-Rafdriver mutations. Data presented here suggest that MageC2 can be a functional targetof the oncogenic MEK/ERK pathway to regulate p53.