Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli

Oncogene. 2006 Mar 2;25(9):1290-8. doi: 10.1038/sj.onc.1209161.

Abstract

The retinoblastoma tumor-suppressor protein (RB) is an important regulator of cell cycle and apoptosis. RB is phosphorylated by cyclin-dependent protein kinase during cell cycle progression. A phosphorylation site mutated (PSM)-RB has previously been shown to cause G1 arrest and to interfere with S phase progression. In this study, we examined the effect of inducible PSM-RB expression on the apoptotic response to three different death stimuli: doxorubicin (DOXO), staurosporine (STS) and tumor necrosis factor (TNF) in Rat-16 cells. Induced expression of PSM-RB attenuated caspase activation by DOXO as a result of cell cycle arrest. STS has been shown to cause RB-dependent G1 arrest or apoptosis; however, expression of PSM-RB did not prevent caspase activation by STS. Surprisingly, induced expression of PSM-RB stimulated the apoptotic response to TNF in Rat-16 cells, which mostly undergo necrosis in the absence of PSM-RB. These results show that PSM-RB exerts disparate effects on apoptotic response to different stimuli, and that cell cycle arrest does not always associate with resistance to apoptosis.

Publication types

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis / genetics*
  • Caspases / metabolism
  • Cell Culture Techniques
  • Cell Cycle
  • Doxorubicin / pharmacology
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Mutation
  • Phosphorylation
  • Rats
  • Retinoblastoma Protein / biosynthesis*
  • Retinoblastoma Protein / genetics*
  • Retinoblastoma Protein / physiology
  • Staurosporine / pharmacology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Antibiotics, Antineoplastic
  • Enzyme Inhibitors
  • Retinoblastoma Protein
  • Tumor Necrosis Factor-alpha
  • Doxorubicin
  • Caspases
  • Staurosporine