Abstract
Deregulated oncogenes such as MYC and RAS are typically insufficient to transform cells on their own due to the activation of pathways that restrain proliferation. Previous studies have shown that oncogenic H-Ras can induce proliferative arrest or senescence, depending on the cellular context. Here, we show that deregulated H-Ras activity can also lead to caspase-independent cell death with features of autophagy. Ras-induced autophagy was associated with upregulation of the BH3-only protein Noxa as well as the autophagy regulator Beclin-1. Silencing of Noxa or Beclin-1 expression reduced Ras-induced autophagy and increased clonogenic survival. Ras-induced cell death was also inhibited by coexpression of Bcl-2 family members that inhibit Beclin-1 function. Ras-induced autophagy was associated with Noxa-mediated displacement of the Bcl-2 family member, Mcl-1, from Beclin-1. Thus, Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death, which represents a mechanism to limit the oncogenic potential of deregulated Ras signals.
Keywords
AutophagyBiologyCell biologyProgrammed cell deathGene silencingDownregulation and upregulationClonogenic assayContext (archaeology)ApoptosisRegulatorCancer researchGeneticsGene
MeSH Terms
Apoptosis Regulatory ProteinsAutophagyAutophagy-Related Protein 5Autophagy-Related Protein 7Base SequenceBeclin-1CaspasesCell LineCell ProliferationCell SurvivalCell TransformationNeoplasticColony-Forming Units AssayEnzyme ActivationExtracellular Signal-Regulated MAP KinasesGene ExpressionGene Knockdown TechniquesGenesbcl-2GenesrasGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHumansMembrane ProteinsMicrotubule-Associated ProteinsMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2RNASmall InterferingSignal TransductionTOR Serine-Threonine KinasesUbiquitin-Activating Enzymes
Affiliated Institutions
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Publication Info
- Year
- 2011
- Type
- article
- Volume
- 42
- Issue
- 1
- Pages
- 23-35
- Citations
- 414
- Access
- Closed
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Cite This
Mohamed Elgendy,
Clare Sheridan,
Gabriela Brumatti
et al.
(2011).
Oncogenic Ras-Induced Expression of Noxa and Beclin-1 Promotes Autophagic Cell Death and Limits Clonogenic Survival.
Molecular Cell
, 42
(1)
, 23-35.
https://doi.org/10.1016/j.molcel.2011.02.009
Identifiers
- DOI
- 10.1016/j.molcel.2011.02.009
- PMID
- 21353614