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.
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Abbreviations
- CPC:
-
chromosomal passenger complex
- INCENP:
-
inner centromere protein
- IAP:
-
inhibitor of apoptosis protein
- CENP-A:
-
centromeric protein A
- Alb-surv−/−:
-
albumin-cre survivinflox/flox
- pHistone H3(S10):
-
phosphorylated Histone H3 at serine 10
- pHistone H3(S28):
-
phosphorylated Histone H3 at serine 28
- pHec-1(S55):
-
phosphorylated highly expressed in cancer protein 1 at serine 55
- pCENP-A(S7):
-
phosphorylated centromeric protein A at serine 7
- VRK-1:
-
vaccinia-related kinase 1
- ALAT:
-
serum alanine-aminotransferase
- ASAT:
-
serum aspartate-aminotransferase
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Acknowledgements
We wish to thank Dr. Yanli Gu for performing the liver resections. Laura Malkus, Mareike Müller and Nicole Macha for their technical assistance. We also want to thank Ms Lucie Horn for her assistance in analyzing the DNA content in hepatocyte nuclei. This study was supported by the DFG (KFO 117, TP B5 (Ba 1730/10-1)).
Authors contributions
Study design: BL, HAB, AM. Data acquisition: SH, SB, DM, GPP, GK, KL, BS. Material support: EMC, AM. Manuscript drafting: SH, JW, EMC, HAB. Important intellectual content: AM.
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Hagemann, S., Wohlschlaeger, J., Bertram, S. et al. Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function. Cell Death Differ 20, 834–844 (2013). https://doi.org/10.1038/cdd.2013.20
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DOI: https://doi.org/10.1038/cdd.2013.20
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