Survivin is upregulated during liver regeneration in rats and humans and is associated with hepatocyte proliferation

Baba, Hideo A.; Wohlschlaeger, Jeremias; Schmitz, Klaus; Nadalin, Silvio; Lang, Hauke; Benesch, Alexandra; Gu, Yanli; Biglarnia, Ali-Reza; Sotiropoulos, Georgios C.; Takeda, Atsushi; Takeda, Nobuakira; Lipinski, Karen von Wnuck; Levkau, Bodo

doi:10.1111/j.1478-3231.2008.01911.x

Cited by 18 publications

(18 citation statements)

References 23 publications

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“…Expression of survivin is associated with inhibition of cell death and is required for cell division (Altieri, 2008). Survivin has recently been reported to be important in liver regeneration following partial hepatectomy (Baba et al , 2009). Within 3 h of acetaminophen administration to wild type mice, we found that survivin protein expression was up-regulated in hepatocyte nuclei located adjacent to portal veins and spreading to necrotic zones in the livers by 24 h. Evidence suggests that expression of survivin is controlled by Cav-1 via the β-catenin-Tcf/Lef-dependent signaling pathway and it has been suggested that the anti-proliferative and pro-apoptotic properties of Cav-1 are due to reduced survivin expression (Torres et al , 2006).…”

Section: Discussionmentioning

confidence: 99%

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

Gardner

Gray

Joseph

et al. 2010

Toxicology and Applied Pharmacology

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Caveolin-1 (Cav-1) is a membrane scaffolding protein which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1 −/− ) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild type mice with acetaminophen (300 mg/ kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1 −/− mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1 −/− mice is not due to alterations in anti-oxidant defense. In wild type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1 −/− mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1 −/− mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

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Section: Discussionmentioning

confidence: 99%

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

Gardner

Gray

Joseph

et al. 2010

Toxicology and Applied Pharmacology

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“…3,4 In regeneration experiments, we could show that the reduced hepatocyte number is likely due to decreased proliferation rather than increased cell death, as no differences in apoptosis were detected. Previous reports demonstrated that depletion of Survivin, inspite of leading to a major defect in mitosis, was not associated with an increase of apoptosis.…”

Section: Alb-survmentioning

confidence: 94%

“…19 In studies conducted in rodents, an increase in Survivin expression after partial hepatectomy was observed at postoperative days 2-3. 3,4 After split liver transplantations in humans, Survivin expression was elevated in the graft at day 5. In both settings, Survivin immunoexpression correlated with proliferation but not with apoptosis.…”

mentioning

confidence: 99%

“…1,2 Survivin is highly expressed in various malignancies, but is also detected in several differentiated adult tissues, especially during proliferation and regenerative processes. [3][4][5][6][7] Recently, it has also been shown that Survivin has several mitotic functions and has a central role in cell division. 2,8 As a member of the chromosomal passenger complex (CPC), Survivin has a crucial role in chromosome segregation during mitosis and cytokinesis.…”

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confidence: 99%

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

et al. 2013

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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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“…163 In addition, survivin, a protein involved in negative regulation of program cell death, has recently been shown to be upregulated during liver regeneration and to mediate hepatocyte proliferation. 183 Finally, TGF-b1, another cytokine found upregulated after partial hepatectomy, has a central role in liver tissue remodeling events. Interestingly, TGF-b1 is involved in liver regeneration termination after liver mass recovery, 162 although its effect might be partly indirect and depend on induction of stellate cell activation and enhanced ECM synthesis (see behind).…”

Section: Liver Regeneration: a Good Reason For Choosing Liver Models mentioning

confidence: 99%

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

et al. 2010

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Mesenchymal stem (stromal) cells (MSCs) are a source of circulating progenitors that are able to generate cells of all mesenchymal lineages and to cover cellular demands of injured tissues. The extent of their transdifferentiation plasticity remains controversial. Cells with MSC properties have been obtained from diverse tissues after purification and expansion in vitro. These cellular populations are heterogeneous and under certain conditions show pluripotent-like properties. MSCs present immunosuppressive and anti-inflammatory features and high migratory capacity toward inflamed or remodeling tissues. In this study we review available data regarding factors and signaling axes involved in the chemoattraction and engraftment of MSCs to an injured tissue or to a tissue undergoing active remodeling. Moreover, experimental evidence in support of uses of MSCs as vehicles of therapeutic genes is discussed. Because of its regenerative capacity and its particular immune properties, the liver is a good model to analyze the potential of MSCbased therapies. Finally, the potential application of MSCs and genetically modified MSCs in liver fibrosis and hepatocellular carcinoma (HCC) is proposed in view of available evidence.

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Survivin is upregulated during liver regeneration in rats and humans and is associated with hepatocyte proliferation

Abstract: Survivin is upregulated in human and rodent liver regeneration and correlates with proliferation, suggesting an association of survivin and cell division.

Cited by 18 publications

References 23 publications

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

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

Mesenchymal stem cells as therapeutic tools and gene carriers in liver fibrosis and hepatocellular carcinoma

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