The ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner.
Survivin, a human inhibitor of apoptosis protein (IAP), plays an important role in both cell cycle regulation and inhibition of apoptosis. Survivin is expressed in cells during the G(2)/M phase of the cell cycle, followed by rapid decline of both mRNA and protein levels at the G(1) phase. It has been suggested that cell cycle-dependent expression of survivin is regulated at the transcriptional level. In this study we demonstrate involvement of the ubiquitin-proteasome pathway in post-translational regulation of survivin. Survivin is a short-lived protein with a half-life of about 30 minutes and proteasome inhibitors greatly stabilise survivin in vivo. Expression of the survivin gene under the control of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during the G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mutation of critical amino acid residues within the baculovirus IAP repeat (BIR) domain or truncation of the N terminus or the C terminus sensitises survivin to proteasome degradation. Together, these results indicate that the ubiquitin-proteasome pathway regulates survivin degradation in a cell cycle-dependent manner and structural changes greatly destabilise the survivin protein.
Zhao
J
J
ICRF Molecular Oncology Unit, Imperial College School of Medicine, Hammersmith Campus, Du Cane Road, London W12 ONN, UK.
Tenev
T
T
Martins
L M
LM
Downward
J
J
Lemoine
N R
NR
D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology*; D016195:G2 Phase / Q000502:physiology; D017353:Gene Deletion; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007668:Kidney / Q000166:cytology; D008239:Lysine / Q000378:metabolism; D008869:Microtubule-Associated Proteins; D008898:Mimosine / Q000494:pharmacology; D008938:Mitosis / Q000502:physiology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016296:Mutagenesis / Q000502:physiology; D009363:Neoplasm Proteins; D015739:Nocodazole / Q000494:pharmacology; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012997:Solvents / Q000494:pharmacology; D000077022:Survivin; D013936:Thymidine / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism*
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D011506:Proteins; D012997:Solvents; D000077022:Survivin; D014452:Ubiquitins; D008898:Mimosine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine; D015739:Nocodazole; D013936:Thymidine; D004121:Dimethyl Sulfoxide