IQUIBICEN   23947
INSTITUTO DE QUIMICA BIOLOGICA DE LA FACULTAD DE CIENCIAS EXACTAS Y NATURALES
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
MageC2: a novel member of the Ras/B-Raf oncogenic pathway to counteract the p53 response in human melanoma
Autor/es:
MICAELA ESCALADA; FRANCO PASCUCCI; MONTE MARTIN; FATIMA LADELFA
Lugar:
Congreso Virtual a distancia
Reunión:
Congreso; XX Reunión Científica anual de la Sociedad Científica Argentina De Investigación Clínica (SAIC); 2020
Resumen:
Ras proteins (H-, N- and K-Ras) transduce proliferation signals from growth-factoractivated receptor tyrosine kinases (RTKs) through the mitogen activated protein kinase(MAPK: Raf/MEK/ERK) pathway. Activating mutations in Ras or B-Raf proto-oncogenes (i.e,RasV12 or B-RafV600E) are frequent in human melanoma. In normal cells oncogenic Rasor B-Raf activates p53 and/or pRb tumor suppressor response. We aimed to study theMAGE-I (Melanoma Antigen Genes-I) proteins involvement in wt-p53 regulation inmelanoma (p53 regulators highly expressed in melanoma).Here, we identified MageC2 protein as a p53 regulator in an oncogene-activated MAPKscontext. First, we observed that MageC2 protein levels respond to serum deprivation incultured cells. Since growth factors activate RTK/Ras, we studied Ras role, and weobserved that RasV12 enhanced MageC2 levels depending on a functional MEK/ERKpathway by PD184352 MEK inhibitor treatment. MageC2 raising did not involve MageC2expression changes and required active proteasome as indicated by MG132 treatment,and accumulated MageC2 was phosphorylated only in threonine as assessed by antiphosphoaminoacids. To study the MageC2 role in p53 regulation activity in oncogeneactivatedMEK/ERK condition, we generated CRISPR/CAS9 mediated MageC2 KO in A375melanoma cells and we regulated MAPK hyperactivity with PD184352 to study p53 activityby its targets (p21, Mdm2 and PUMA) quantification, and we observed that MageC2 playsa key role as a downstream target of the B-Raf/MAPK oncogenic pathway by controllingthe p53 response. Finally, gene expression analysis of TCGA skin cutaneous melanoma(n=448) through Cbioportal showed a significant inverse correlation between highMageC2 expression (RSEM>1000) and p53 targets expression (p21, BAX and PUMA) onlyin a Ras/B-Raf hyperactivated context (n=263). In conclusion, we propose that Ras or B-Rafdownregulates wt-p53 activity by increasing MageC2 protein levels through the MAPKpathway.