Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function

Abstract

The chromosomal passenger complex (CPC) acts as a key regulator of mitosis, preventing asymmetric segregation of chromosomal material into daughter cells. The CPC is composed of three non-enzymatic components termed Survivin, the inner centromere protein (INCENP) and Borealin, and an enzymatic component, Aurora B kinase. Survivin is necessary for the appropriate separation of sister chromatids during mitosis and is involved in liver regeneration, but its role in regenerative processes is incompletely elucidated. Whether Survivin, which is classified as an inhibitor of apoptosis protein (IAP) based on domain composition, also has a role in apoptosis is controversial. The present study examined the in vivo effects of Survivin ablation in the liver and during liver regeneration after 70% hepatectomy in a hepatocyte-specific knockout mouse model. The absence of Survivin caused a reduction in the number of hepatocytes in the liver, together with an increase in cell volume, macronucleation and polyploidy, but no changes in apoptosis. During liver regeneration, mitosis of hepatocytes was associated with mislocalization of the members of the CPC, which were no longer detectable at the centromere despite an unchanged protein amount. Furthermore, the loss of survivin in regenerating hepatocytes was associated with reduced levels of phosphorylated Histone H3 at serine 28 and abolished phosphorylation of CENP-A and Hec1 at serine 55, which is a consequence of decreased Aurora B kinase activity. These data indicate that Survivin expression determines hepatocyte number during liver development and liver regeneration. Lack of Survivin causes mislocalization of the CPC members in combination with reduced Aurora B activity, leading to impaired phosphorylation of its centromeric target proteins and inappropriate cytokinesis.

Intranuclear inclusions in hepatocellular carcinoma contain autophagy‐associated proteins and correlate with prolonged survival

“…These inclusions were immunohistochemically positive for proteins involved in proteosomal degradation and autophagy suggesting that these inclusions serve as a place for protein degradation. In an earlier study using transgenic mice with deletion of survivin in hepatocytes we detected numerous nuclear inclusions containing proteins of the chromosomal passenger complex (CPC); these proteins are partners of survivin. While in wild type mice the proteins of the CPC are located at the centromere region of chromosomes, in survivin KO mice these proteins were no longer detectable at the centromeres but, strikingly, instead in nuclear inclusions .…”

“…In an earlier study using transgenic mice with deletion of survivin in hepatocytes we detected numerous nuclear inclusions containing proteins of the chromosomal passenger complex (CPC); these proteins are partners of survivin. While in wild type mice the proteins of the CPC are located at the centromere region of chromosomes, in survivin KO mice these proteins were no longer detectable at the centromeres but, strikingly, instead in nuclear inclusions . It is not known why the lack of survivin causes mislocalisation of the CPC proteins in nuclear inclusions but it can be supposed that these proteins may be degraded in the inclusions.…”

Bacterial outer membrane vesicles: New insights and applications

“…The composition of the lipid bilayer of OMVs retains the asymmetry observed in bacterial OM, with complex lipids in the outermost layer mounted on a uniform glycerophospholipid inner layer. Recently, a few examples of double bilayer OMVs have been observed in Bacillus anthracis (Rivera et al, 2010), Shewanella vesiculosa M 7T (Perez-Cruz et al, 2013), Ahrensia kielensis, and Pseudoalteromonas marina (Hagemann et al, 2013) whose detailed discussion is not in the scope of this review.…”

“…Deletion of nlp causes change in PG dynamics and affects Lpp cross-linking. This induces hyper-vesiculation A. baumanii(Hagemann et al, 2013); E. coli(Moon et al, 2012)…”

Detection of high levels of Survivin–immunoglobulin M immune complex in sera from hepatitis C virus infected patients with cirrhosis

“…[22][23][24] However, several papers describe diverse expression, cellular localization and prognostic significance of Survivin in cirrhotic liver and HCC. [31][32][33][34][35][36][37][38] Actually, compared to healthy subject, Survivin-IgM IC was found significantly higher in all patients with liver diseases included in the study, suggesting a modification correlated to liver dysfunction; moreover, recent papers reported a link of Survivin to liver regeneration, 39,40 that extensively occurs after liver damage. However, the Survivin-IgM IC values were exceptionally high in HCV-related cirrhosis, and, unexpectedly, those of HCV + HCC patients were lower compared to those detected in cirrhotic patients.…”