The role of survivin in liver regeneration

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Liver regeneration after hepatectomy is a complex regulated process involving cell proliferation and apoptosis. A major regulator of both molecular processes is survivin, a member of the inhibitor of the apoptosis (IAP) family. Survivin directly inhibits the cell death proteases of the cell, the caspases, and controls mitosis and chromosome segregation via its function as chromosomal passenger. Neither the impact of lAPs in general nor that of survivin in particular in liver regeneration is currently known. Our preliminary work in a 70% liver resection rat model has shown a dramatic induction of survivin mRNA (~40-fold) after 24 hours as measured by real-time PCR. Survivin protein expression levels in hepatocytes were also increased as detected by immunohistochemistry and western blotting. The transcriptional induction of survivin correlated significantly with the proliferation of hepatocytes detected by the proliferation marker Ki-67. Surprisingly, no correlation could be observed with the extent of apoptosis. In line with the animal study, we were able to show survivin immuno-expression in the human regeneration liver, which correlates with hepatocyte proliferation but not with apoptosis. To investigate the role of survivin in liver regeneration we will employ three different genetic mouse models: (1) a heterozygous survivin K0+/"; (2) a hepatocyte-specific survivin KO"'"; and (3) an inducible hepatocytespecific survivin KO"'". Complementary studies with inducing survivin will give us new insights of the role of survivin in the regenerative response of the liver, and identify approaches to selectively target survivin for the benefit of living donor liver transplantation.