INVESTIGADORES
ROPOLO Alejandro Javier
artículos
Título:
A novel AKT1-GLI3-VMP1 pathway mediates KRAS-induced autophagy in cancer cells.
Autor/es:
LO RE, A.; FERNANDEZ-BARRENA, M.G.; ALMADA, L. L.; MILLS, L.; ELSAWA, S. F.; LUND, G.; ALEJANDRO JAVIER ROPOLO; MOLEJÓN, M. I.; VACCARO, M. I.; FERNANDEZ-ZAPICO, M. E.
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Editorial:
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Referencias:
Lugar: Rockville, Maryland; Año: 2012 vol. 287 p. 25325 - 25334
ISSN:
0021-9258
Resumen:
Autophagy is an evolutionarily conserved degradation process of cytoplasmic cellular constituents. It has been suggested that autophagy plays a role in tumor promotion and progression downstream oncogenic pathways; however, the molecular mechanisms underlying this phenomenon have not been elucidated. Here, we describe a novel signaling pathway initiated by the oncogene KRAS inducing the in vitro and in vivo expression of VMP1, a molecule needed for the formation of the authophagosome and capable of inducing autophagy, even under nutrient-replete conditions. RNAi experiments demonstrated that KRAS requires VMP1 to induce autophagy. Analysis of the mechanisms identified GLI3, a transcription factor regulated by the Hedgehog pathway, as an effector of KRAS signaling. GLI3 regulates autophagy as well as the expression and promoter activity of VMP1 in a Hedgehog-independent manner. Chromatin immunoprecipitation assays demonstrated that GLI3 binds to the VMP1 promoter and complex with the histone acetyltransferase p300 to regulate this promoter activity. Knockdown of p300 impaired KRAS- and GLI3-induced activation of this promoter. Finally, we identified the PI3K-AKT1 pathway as the signaling pathway mediating the expression and promoter activity of VMP1 upstream of GLI3-p300 complex. Together, these data provide evidence of a new regulatory mechanism involved in autophagy that integrates this cellular process into the molecular network of events regulating oncogene-induced autophagy.