Role of p53 in cell cycle regulation and apoptosis following exposure to proteasome inhibitors.
In this study, we explored what effect inhibitors of the 26S proteasome have on cell cycle distribution and induction of apoptosis in human skin fibroblasts and colon cancer cells differing in their p53 status. We found that proteasome inhibition resulted in nuclear accumulation of p53. This was surprising because it is thought that the degradation of p53 is mediated by cytoplasmic 26S proteasomes. Nuclear accumulation of p53 was accompanied by the induction of both p21WAF1 mRNA and protein as well as a decrease in cells entering S phase. Interestingly, cells with compromised p53 function showed a marked increase in the proportion of cells in the G2-M phase of the cell cycle and an attenuated induction of apoptosis after proteasome inhibition. Taken together, our results suggest that proteasome inhibition results in nuclear accumulation of p53 and a p53-stimulated induction of both G1 arrest and apoptosis.
Chen
F
F
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0396, USA.
Chang
D
D
Goh
M
M
Klibanov
S A
SA
Ljungman
M
M
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007399:Interphase / Q000187:drug effects / Q000502:physiology*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012867:Skin / Q000166:cytology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine