Regulation of the proapoptotic ARTS protein by ubiquitin-mediated degradation.
ARTS is a mitochondrial protein that promotes apoptosis induced by a variety of proapoptotic stimulators. ARTS induces apoptosis, at least in part, through binding to and antagonizing IAPs (inhibitors of apoptosis proteins). As a result of ARTS binding to IAPs, caspase inhibition is removed and apoptosis can be executed. Here we show that high cellular levels of ARTS protein sensitize cells toward apoptosis. Accordingly, in healthy cells ARTS levels are kept low through constant ubiquitin-mediated degradation. Upon proapoptotic stimuli, the ubiquitination process is inhibited, resulting in increased levels of ARTS. Increased ARTS in turn leads to a decrease of Bcl-2 and Bcl-xL protein levels, cytochrome c release from mitochondria and apoptosis.
Lotan
Rona
R
Apoptosis and Cancer Research Laboratory, Pathology Department, Rambam Medical Center, Bat-Galim, Haifa 31096, Israel.
Rotem
Asaf
A
Gonen
Hedva
H
Finberg
John P M
JP
Kemeny
Stav
S
Steller
Hermann
H
Ciechanover
Aaron
A
Larisch
Sarit
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D058112:Septins; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D003598:Cytoskeletal Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D051020:bcl-X Protein; D045304:Cytochromes c; D020558:GTP Phosphohydrolases; C492027:SEPTIN4 protein, human; D058112:Septins