Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells.

Academic Article


  • 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 provide both in vitro and in vivo evidence of a novel signaling pathway whereby the oncogene KRAS induces the 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 complexes with the histone acetyltransferase p300 to regulate 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 the 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.
  • Authors

  • Lo Ré, Andrea E
  • Fernández-Barrena, Maite G
  • Almada, Luciana L
  • Mills, Lisa D
  • Elsawa, Sherine
  • Lund, George
  • Ropolo, Alejandro
  • Molejon, Maria I
  • Vaccaro, Maria I
  • Fernandez-Zapico, Martin E
  • Status

    Publication Date

  • July 20, 2012
  • Published In


  • Animals
  • Autophagy
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Hedgehog Proteins
  • Humans
  • Kruppel-Like Transcription Factors
  • Membrane Proteins
  • Mice
  • Neoplasms
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins p21(ras)
  • Response Elements
  • Signal Transduction
  • Zinc Finger Protein Gli3
  • p300-CBP Transcription Factors
  • ras Proteins
  • Digital Object Identifier (doi)

    Start Page

  • 25325
  • End Page

  • 25334
  • Volume

  • 287
  • Issue

  • 30