Regulation of apoptosis by Bcl-2 cysteine oxidation in human lung epithelial cells

Mol Biol Cell. 2013 Mar;24(6):858-69. doi: 10.1091/mbc.E12-10-0747. Epub 2013 Jan 30.


Hydrogen peroxide is a key mediator of oxidative stress known to be important in various cellular processes, including apoptosis. B-cell lymphoma-2 (Bcl-2) is an oxidative stress-responsive protein and a key regulator of apoptosis; however, the underlying mechanisms of oxidative regulation of Bcl-2 are not well understood. The present study investigates the direct effect of H2O2 on Bcl-2 cysteine oxidation as a potential mechanism of apoptosis regulation. Exposure of human lung epithelial cells to H2O2 induces apoptosis concomitant with cysteine oxidation and down-regulation of Bcl-2. Inhibition of Bcl-2 oxidation by antioxidants or by site-directed mutagenesis of Bcl-2 at Cys-158 and Cys-229 abrogates the effects of H2O2 on Bcl-2 and apoptosis. Immunoprecipitation and confocal microscopic studies show that Bcl-2 interacts with mitogen-activated protein kinase (extracellular signal-regulated kinase 1/2 [ERK1/2]) to suppress apoptosis and that this interaction is modulated by cysteine oxidation of Bcl-2. The H2O2-induced Bcl-2 cysteine oxidation interferes with Bcl-2 and ERK1/2 interaction. Mutation of the cysteine residues inhibits the disruption of Bcl-2-ERK complex, as well as the induction of apoptosis by H2O2. Taken together, these results demonstrate the critical role of Bcl-2 cysteine oxidation in the regulation of apoptosis through ERK signaling. This new finding reveals crucial redox regulatory mechanisms that control the antiapoptotic function of Bcl-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Antioxidants / pharmacology
  • Apoptosis* / drug effects
  • Catalase / metabolism
  • Cell Line
  • Cysteine / metabolism*
  • Down-Regulation
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glutathione / pharmacology
  • Humans
  • Hydrogen Peroxide / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Lung / cytology*
  • Lung / drug effects
  • Lung / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mutation
  • Oxidation-Reduction
  • Oxidative Stress
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reactive Oxygen Species / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism*


  • Antioxidants
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Hydrogen Peroxide
  • Catalase
  • Extracellular Signal-Regulated MAP Kinases
  • Glutathione
  • Cysteine
  • Acetylcysteine