Reactive oxygen species (ROS) control the expression of Bcl-2 family proteins by regulating their phosphorylation and ubiquitination

Cancer Sci. 2004 Aug;95(8):644-50. doi: 10.1111/j.1349-7006.2004.tb03323.x.


We examined the influence of ROS on the phosphorylation and complex formation of Bcl-2 family proteins in Mn-superoxide dismutase (SOD) antisense-transfected squamous cell carcinoma cells, OSC-4 cells. The increase of intracellular ROS level induced by cis-diamminedichloroplatinum (CDDP) and gamma-ray treatment was greater in antisense-transfected cells than in control vector-transfected cells, and apoptosis was more extensively induced in the former. Antisense-transfected cells expressed high levels of Bax and Bak, but low levels of Bcl-2 and Bcl-XL when treated with CDDP, peplomycin, 5-fluorouracil or gamma-rays. After treatment with these agents, the phosphorylation of protein kinase A, Bcl-2 (Thr56) and Bad (Ser155) was increased, especially in antioxidant (N-acetylcysteine and pyrrolidine dithiocarbamate)-pretreated control cells, but the phosphorylation levels were very low in the antisense-transfected cells. Bcl-2 ubiquitination was increased, but ubiquitination of Bad and Bax was decreased in the antisense-transfected cells, although their ubiquitination was increased by the antioxidants. These results reveal that ROS induce apoptosis by regulating the phosphorylation and ubiquitination of Bcl-2 family proteins, resulting in increased proapoptotic protein levels and decreased antiapoptotic protein expression.

MeSH terms

  • Antineoplastic Agents / toxicity
  • Apoptosis / drug effects*
  • Carcinoma, Squamous Cell / pathology*
  • Cisplatin / toxicity
  • Humans
  • Mouth Neoplasms / pathology*
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Reactive Oxygen Species / pharmacology*
  • Transfection
  • Tumor Cells, Cultured / pathology*
  • Ubiquitins / metabolism


  • Antineoplastic Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • Ubiquitins
  • Cisplatin