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 bee n suggested that cell cycle-dependent expression of survivin is regulated a t the transcriptional level, In this study we demonstrate involvement of the ubiquitin-proteasome pathwa y in post-translational regulation of survivin, Survivin is a short-lived p rotein with a half-life of about 30 minutes and proteasome inhibitors great ly stabilise survivin in vivo. Expression of the survivin gene under the co ntrol of the CMV promoter cannot block cell cycle-dependent degradation of the protein. Proteasome inhibitors can block survivin degradation during th e G(1) phase and polyubiquitinated derivatives can be detected in vivo. Mut ation of critical amino acid residues within the baculovirus IAP repeat (BI R) domain or truncation of the N terminus or the C terminus sensitises surv ivin to proteasome degradation. Together, these results indicate that the u biquitin-proteasome pathway regulates survivin degradation in a cell cycle- dependent manner and structural changes greatly destabilise the survivin pr otein.