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

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

Research output: Contribution to journalArticle

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Abstract

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 ofVMP1upstream 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.

Original languageEnglish (US)
Pages (from-to)25325-25334
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number30
DOIs
StatePublished - Jul 20 2012

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Autophagy
Oncogenes
Cells
Histone Acetyltransferases
Neoplasms
Phosphatidylinositol 3-Kinases
Nutrients
Chromatin
Tumors
Assays
Transcription Factors
Chemical activation
Degradation
Molecules
Chromatin Immunoprecipitation
RNA Interference
Experiments
Food

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Lo Ré, A. E., Fernández-Barrena, M. G., Almada, L. L., Mills, L. D., Elsawa, S. F., Lund, G., ... Fernandez-Zapico, M. E. (2012). Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. Journal of Biological Chemistry, 287(30), 25325-25334. https://doi.org/10.1074/jbc.M112.370809

Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. / Lo Ré, Andrea E.; Fernández-Barrena, Maite G.; Almada, Luciana L.; Mills, Lisa D.; Elsawa, Sherine F.; Lund, George; Ropolo, Alejandro; Molejon, Maria I.; Vaccaro, Maria I.; Fernandez-Zapico, Martin E.

In: Journal of Biological Chemistry, Vol. 287, No. 30, 20.07.2012, p. 25325-25334.

Research output: Contribution to journalArticle

Lo Ré, AE, Fernández-Barrena, MG, Almada, LL, Mills, LD, Elsawa, SF, Lund, G, Ropolo, A, Molejon, MI, Vaccaro, MI & Fernandez-Zapico, ME 2012, 'Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells', Journal of Biological Chemistry, vol. 287, no. 30, pp. 25325-25334. https://doi.org/10.1074/jbc.M112.370809
Lo Ré AE, Fernández-Barrena MG, Almada LL, Mills LD, Elsawa SF, Lund G et al. Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. Journal of Biological Chemistry. 2012 Jul 20;287(30):25325-25334. https://doi.org/10.1074/jbc.M112.370809
Lo Ré, Andrea E. ; Fernández-Barrena, Maite G. ; Almada, Luciana L. ; Mills, Lisa D. ; Elsawa, Sherine F. ; Lund, George ; Ropolo, Alejandro ; Molejon, Maria I. ; Vaccaro, Maria I. ; Fernandez-Zapico, Martin E. / Novel AKT1-GLI3-VMP1 pathway mediates KRAS oncogene-induced autophagy in cancer cells. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 30. pp. 25325-25334.
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