p53-dependent apoptosis induced by proteasome inhibition in mammary epithelial cells.
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.
MacLaren
A P
AP
Sir Alastair Currie CRC Laboratories, Molecular Medicine Centre, Western General Hospital, Crewe Road, Edinburgh, EH2 4XU, UK. A.Maclaren@beatson.gla.ac.uk
Chapman
R S
RS
Wyllie
A H
AH
Watson
C J
CJ
D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007976:Leupeptins / Q000494:pharmacology*; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D017304:Annexin A5; D000957:Antigens, Viral, Tumor; D007976:Leupeptins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde