p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells

Cell Death Differ. 2001 Mar;8(3):210-8. doi: 10.1038/sj.cdd.4400801.


We have examined the effects of inhibition of the 26S proteasome in a murine mammary cell line, KIM-2 cells using the peptide aldehyde inhibitor MG132. These studies have demonstrated a clear requirement for proteasome function in cell viability. Induction of apoptosis was observed following MG132 treatment in KIM-2 cells and this death was shown to be dependent on the cell actively traversing the cell cycle. KIM-2 cells were generated using a temperature sensitive T-antigen (Tag) and studies at the permissive temperature (33 degrees C) have shown that a Tag binding protein was essential for this apoptotic response. Studies in two additional cell lines, HC11, which is a mammary epithelial cell line carrying mutant p53 alleles and p53 null ES cells suggest that p53 is actively required for the apoptosis induced as a consequence of proteasome inhibition. These results suggest a pivotal role for the 26S proteasome degradation pathway in progression through the cell cycle in proliferating cells.

MeSH terms

  • Animals
  • Annexin A5 / analysis
  • Antigens, Viral, Tumor / biosynthesis
  • Antigens, Viral, Tumor / physiology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Cycle / physiology
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • Leupeptins / pharmacology*
  • Mammary Glands, Animal / cytology*
  • Mammary Glands, Animal / drug effects
  • Mammary Glands, Animal / enzymology
  • Mice
  • Protease Inhibitors / pharmacology*
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors*
  • Tumor Suppressor Protein p53 / biosynthesis
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology*


  • Annexin A5
  • Antigens, Viral, Tumor
  • Leupeptins
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Tumor Suppressor Protein p53
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde