Proteasomes modulate balance among proapoptotic and antiapoptotic Bcl-2 family members and compromise functioning of the electron transport chain in leukemic cells.
The mechanism underlying apoptosis induced by proteasome inhibition in leukemic Jurkat and Namalwa cells was investigated in this study. The proteasome inhibitor lactacystin differentially regulated the protein levels of proapoptotic Bcl-2 family members and Bik was accumulated at the mitochondria. Bik overexpression sufficed to induce apoptosis in these cells. Detailed examination along the respiration chain showed that lactacystin compromised a step after complex III, and exogenous cytochrome c could overcome this compromise. Probably as a result, the succinate-stimulated generation of mitochondrial membrane potential was significantly diminished. Bcl-x(L) interacted with Bik in the cells, and Bcl-x(L) overexpression prevented cytochrome c leakage out of the mitochondria, corrected the mitochondrial membrane potential defect, and protected the cells from apoptosis. These results show that proteasomes can modulate apoptosis of lymphocytes by affecting the half-life of Bcl-2 family members, Bik being one of them.
Marshansky
V
V
Research Center, Notre-Dame Hospital, Center hospitalier universitaire de l'Université de Montréal, University of Montreal, Montreal, Canada. marshanv@receptor.mgh.harvard.edu
Wang
X
X
Bertrand
R
R
Luo
H
H
Duguid
W
W
Chinnadurai
G
G
Kanaan
N
N
Vu
M D
MD
Wu
J
J
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D003546:Cysteine Endopeptidases / Q000378:metabolism / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000276:immunology; D019169:Jurkat Cells; D015448:Leukemia, B-Cell / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008564:Membrane Potentials / Q000276:immunology; D008565:Membrane Proteins; D008928:Mitochondria / Q000201:enzymology / Q000276:immunology; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010447:Peptide Hydrolases / Q000378:metabolism; D010539:Permeability; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; C096820:BIK protein, human; C494813:Bcl2l1 protein, rat; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C067713:lactacystin; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C108711:DEVDase; D000111:Acetylcysteine