Regulation of MAGE tumor proteins by oncogenes and oncosuppressors

JULIETA LAISECA; MARIA FATIMA LADELFA; FRANCO PASCUCCI; GASTON AMATO; MARIA FERNANDA TOLEDO; MARTIN MONTE

Capital Federal

Congreso; Reunion Anual de la SAIC; 2017

MAGE-Igenes expression is restricted to tumor and male germ cells. In the last yearsour group and others characterized different members of the Mage-I family,showing low functional redundancy, despite their high sequence homology.Herewe demonstrate that similarly to we reported for MageA2, MageC2 represses p53transcriptional activity (3.0 fold) in a HDAC-dependent manner throughtrichostatin A (TSA) treatment.Wealso identified two potential candidates able to regulate MAGE function: p14ARFtumor-suppressor and the oncogene RASV12. We observed that p14ARF expressionsignificantly reverted both MageC2 and MageA2 repressive function of ectopicallyexpressed p53 using DKO cells (murine embryonic fibroblasts p53-/-,mdm2-/-) and therefore in an Mdm2-independent fashion. Western Blot assayshowed 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 butno significant degradation was observed. On the contrary, RasV12 expressioncaused an increase in MageA2 and MageC2 protein levels. The effect of RASV12 onMageC2 protein was reflected in a greater inhibition of p53 when MageC2 is co-expressedwith RasV12. Furthermore, the stabilization of MageC2 by RASV12 stronglyprevents its degradation by p14ARF. Our observations suggest for the first timethat MAGE-I tumor proteins could be targeted by oncogenes andtumor-suppressors. However, as demonstrated here, RASV12 oncogene can protectMageC2 from p14ARF degradation thus enhancing MageC2 ability in repressing p53tumor-suppressor function. Altogether, our results uncover a novel notion whereoncogenes could enhance their tumor-prone functions through MAGE proteins.