Cooperation between the mitogen-activated protein kinases (MAPK) pathway and the tumoral protein MageC2

PASCUCCI, FRANCO A.; MONTE, MARTÍN; LADELFA, M FÁTIMA; AMATO GE

Mar del Plata

Congreso; LXIII Reunión Científica de la Sociedad Argentina de Investigación Clínica (SAIC).; 2018

Sociedad Argentina de Investigaciones Clínicas

MAGE-I genes expression is restricted to tumor and male germ cells. MAGE-C2, a MAGE family member, isfrequently expressed in a wide range of solid tumors and is associated with a non-favourable clinicalcourse. We recently detected Ras as a potential oncogene that collaborates with MageC2, increasing itsstabilty and activity (as repressor of p53 function).Here, we explored two of the main cellular pathways in which the RAS protein operates: the mitogenactivatedprotein kinases (MAPK) and phosphoinositide-3 kinase (PI3K) pathways and we observed that themain pathway by which Ras stabilizes MageC2 is the MAPK:?The ability of activated Ras to enhance transfected Myc-MageC2 protein stability was severelyimpaired by the MEK inhibitor PD098059, but it was not affected by the Akt inhibitor LY294002 (similarbehavior was seen by inhibiting both pathways in human melanoma A375 cells expressing endogenousMageC2).?Transfected Myc-MageC2 stability was strongly increased by activation of endogenous Raf-1 (byPhorbol 12-myristate 13-acetate-PMA treatment, a PKC activator).?Transfection with a constitutive active ERK1 also increased Myc-MageC2 stability.We explored if ERK activities lead to MageC2 stabilization:? S85A/S86A MageC2* mutant was still up-regulated after expression of RasV12. Furthermore, we didnot observe MageC2/ERK interaction in an immunoprecipitation assay.(*S85 and S86 are within a consensus phosphorylation sequence for the ERK kinase)Finally inhibition of ERK?sdownstream signaling: RSK (ribosomal S6 kinases), was unable tu umpair Myc-MageC2 stabilization with Ras activation.The mechanism by which the MAPK pathway stabilizes MageC2 is still under study. Our findings have animportant biological relevance, since it proposes for the first time that MageC2 tumor protein could act as alink between the activation of the Ras oncogene and the negative regulation of p53, thus enhancing theoncogenic effect of Ras.