IBIMOL   23987
INSTITUTO DE BIOQUIMICA Y MEDICINA MOLECULAR PROFESOR ALBERTO BOVERIS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
E2F1, the Transcription Factor Related to Proliferation and Cell Death, Mediates Activation of Vmp1 Gene Promoter Inducing Autophagy in Pancreatic Tumor Cells
Autor/es:
ALEJANDRO JAVIER ROPOLO; GIOVENCO, M.; LO RE, A.; MOLEJÓN, M. I.; CATRINACIO, C.; BOGGIO, V.; VACCARO, M. I.
Lugar:
Miami, Florida
Reunión:
Congreso; 44th Meeting of the American Pancreatic Association; 2013
Institución organizadora:
American Pancreatic Association
Resumen:
Autophagy is an evolutionarily preserved degradation process of cytoplasmic cellular constituents, which participates in cell response to disease. We characterized VMP1 (Vacuole Membrane Protein 1) as an essential autophagy related-protein that mediates autophagy in pancreatic diseases. Gemcitabine treatment induced early expression of VMP1 and autophagy in pancreatic cancer cells. However, the regulatory pathways that control vmp1 gene expression and autophagy in pancreatic tumor cells are not fully understood. The retinoblastoma pathway is often inactivated in human tumors resulting in deregulated E2F activity that can induce both proliferation and cell death. E2F1 expression has been correlated with higher tumor grade and worse patient survival in PDAC. The activation of E2F1 was reported to up-regulate the expression of three autophagy genes (LC3, ATG1 and ATG5) and a damageregulated autophagy modulator (DRAM). The aim of this work is to evaluate the effect of E2F1 on VMP1 expression in pancreatic tumor cells. We found that overexpression of E2F1 transcription factor in Panc-1 and MiaPaCa-2 pancreatic tumor cells induces VMP1 expression. We also demonstrated that E2F1 expression induces autophagy analyzed by the increasing number of RFP-LC3 positive cells with a punctate staining. Moreover, we showed that p300, a classical co-activator transcription factor, cooperates with E2F1 in VMP1 promoter regulation. Conversely, RNAi knockdown of p300 impairs E2F1 induced activation of this promoter. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to VMP1 promoter when cells were submitted to gemcitabine treatment. Together these data provide evidence that E2F1 is a new regulatory factor modulating autophagy in pancreatic tumor cells. The knowledge of the mechanism of response to Gemcitabine treatment by tumor cells will improve disease therapeutics.