2. Regulation of MAGE tumor proteins by oncogenes and oncosuppressors

LADELFA MF; MONTE M; PASCUCCI FA; AMATO GE

Congreso; LXII Reunión Científica de la Sociedad Argentina de Investigación Clínica (SAIC).; 2017

MAGE-I genes expression is restricted to tumor and male germ cells. In the last years our group and others characterized different members of the Mage-I family, showing low functional redundancy, despite their high sequence homology.Here we demonstrate that similarly to we reported for MageA2, MageC2 represses p53 transcriptional activity (3.0 fold) in a HDAC-dependent manner through trichostatin A (TSA) treatment.We also identified two potential candidates able to regulate MAGE function: p14ARF tumor-suppressor and the oncogene RASV12. We observed that p14ARF expression significantly reverted both MageC2 and MageA2 repressive function of ectopically expressed p53 using DKO cells (murine embryonic fibroblasts p53-/-, mdm2-/-) and therefore in an Mdm2-independent fashion. Western Blot assay showed that MageC2 is degraded by p14ARF expression depending on proteasome activity (60% decrease reverted by MG132, a proteasome inhibitor). On the other side, immunofluorescence showed that MageA2 is relocalized to the nucleoli by p14ARF but no significant degradation was observed. On the contrary, RasV12 expression caused an increase in MageA2 and MageC2 protein levels. The effect of RASV12 on MageC2 protein was reflected in a greater inhibition of p53 when MageC2 is co-expressed with RasV12. Furthermore, the stabilization of MageC2 by RASV12 strongly prevents its degradation by p14ARF. Our observations suggest for the first time that MAGE-I tumor proteins could be targeted by oncogenes and tumor-suppressors. However, as demonstrated here, RASV12 oncogene can protect MageC2 from p14ARF degradation thus enhancing MageC2 ability in repressing p53 tumor-suppressor function. Altogether, our results uncover a novel notion where oncogenes could enhance their tumor-prone functions through MAGE proteins.