Proteasome-dependent regulation of p21WAF1/CIP1 expression.
Proteasome-dependent degradation of regulatory proteins is a known mechanism of cell cycle control. We found that the proteasome-specific inhibitor lactacystin (LC) induced expression of the cell cycle inhibitor p21WAF1/CIP1 in human cancer cells regardless of their p53 status. Both wild-type (wt) p53 and p21 protein levels increased by two hours in wt p53 containing cells, whereas mutant (mt) p53 levels decreased and the increase in p21 levels was delayed to 6 hr following inhibition of proteolysis by LC in mt p53 expressing cells. We found that wt but not mt p53 expressing cells increased p21 mRNA and p21-promoter reporter levels following LC exposure, suggesting transcriptional induction of p21. Inhibition of protein synthesis by cycloheximide demonstrated increased p21 protein half-life in the presence of LC in mutant p53 containing cells. p21 induction was correlated with the cytostatic effects of LC. The results suggest that p21 protein expression could be increased by transcriptional mechanisms as well as inhibition of proteolysis by LC.
Blagosklonny
M V
MV
Howard Hughes Medical Institute, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
Wu
G S
GS
Omura
S
S
el-Deiry
W S
WS
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D003110:Colonic Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D003609:Dactinomycin / Q000494:pharmacology; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000096:biosynthesis; D009097:Multienzyme Complexes / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis / Q000187:drug effects; D011994:Recombinant Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; C067713:lactacystin; D003609:Dactinomycin; D003513:Cycloheximide; D008156:Luciferases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine