Oncogenic Ras-induced expression of Noxa and Beclin-1 promotes autophagic cell death and limits clonogenic survival

Mol Cell. 2011 Apr 8;42(1):23-35. doi: 10.1016/j.molcel.2011.02.009. Epub 2011 Feb 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics*
  • Autophagy / genetics*
  • Autophagy / physiology
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Base Sequence
  • Beclin-1
  • Caspases / metabolism
  • Cell Line
  • Cell Proliferation
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Cell Transformation, Neoplastic / genetics
  • Colony-Forming Units Assay
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression
  • Gene Knockdown Techniques
  • Genes, bcl-2
  • Genes, ras*
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics*
  • Microtubule-Associated Proteins / antagonists & inhibitors
  • Microtubule-Associated Proteins / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • Ubiquitin-Activating Enzymes / antagonists & inhibitors
  • Ubiquitin-Activating Enzymes / genetics

Substances

  • ATG5 protein, human
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Protein 5
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • MTOR protein, human
  • Glycogen Synthase Kinase 3 beta
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3
  • Caspases
  • ATG7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes