CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy.

Greenbaum, Linda E.; Li, Wei; Cressman, Drew E.; Peng, Yong; Ciliberto, Gennaro; Poli, Valeria; Taub, Rebecca

doi:10.1172/jci3135

Cited by 261 publications

(243 citation statements)

References 57 publications

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“…It has been previously reported that regaining of liver mass is a general phenomenon in mouse models despite the fact that they are defective in liver regeneration; this mostly likely results from cell size increase (i.e., hypertrophy of hepatocytes; refs. [22][23][24][25]. Interestingly, the ratios of regenerating liver to body weight for the Aurora-A;p53−/− mice were significantly higher than for the other genotypes of mice 5 days after hepatectomy (Fig.…”

Section: Premitotic Arrest and Necrosis Caused By Aurora-a Overexpresmentioning

confidence: 86%

Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration

Yang

Chou

et al. 2009

Molecular Cancer Research

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Aurora-A, a serine-threonine kinase, is frequently overexpressed in human cancers, including hepatocellular carcinoma. To study the phenotypic effects of Aurora-A overexpression on liver regeneration and tumorigenesis, we generated transgenic mice overexpressing human Aurora-A in the liver. The overexpression of Aurora-A after hepatectomy caused an earlier entry into S phase, a sustaining of DNA synthesis, and premitotic arrest in the regenerating liver. These regenerating transgenic livers show a relative increase in binuclear hepatocytes compared with regenerating wild-type livers; in addition, multipolar segregation and trinucleation could be observed only in the transgenic hepatocytes after hepatectomy. These results together suggest that defects accumulated after first round of the hepatocyte cell cycle and that there was a failure to some degree of cytokinesis. Interestingly, the p53-dependent checkpoint was activated by these abnormalities, indicating that p53 plays a crucial role during liver regeneration. Indeed, the premitotic arrest and abnormal cell death, mainly necrosis, caused by Aurora-A overexpression were genetically rescued by p53 knockout. However, trinucleation of hepatocytes remained in the regenerating livers of the transgenic mice with a p53 knockout background, indicating that the abnormal mitotic segregation and cytokinesis failure were p53 independent. Moreover, overexpression of Aurora-A in transgenic liver led to a low incidence (3.8%) of hepatic tumor formation after a long latency period. This transgenic mouse model provides a useful system that allows the study of the physiologic effects of Aurora-A on liver regeneration and the genetic pathways of Aurora-A-mediated tumorigenesis in liver.

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Section: Premitotic Arrest and Necrosis Caused By Aurora-a Overexpresmentioning

confidence: 86%

Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration

Yang

Chou

et al. 2009

Molecular Cancer Research

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“…Although the molecular mechanisms responsible for such regulation remain unknown, a number of candidates are worthy of consideration. For example, expression of CCAAT enhancer binding protein (C/EBP) transcription factors, including C/EBP␤ and C/EBP␦, are increased during and essential for normal liver regeneration 34 and are also important regulators of adipocyte differentiation. 35 Thus, modulation of C/EBP activity may determine adipogenic changes during early liver regeneration.…”

Section: Discussionmentioning

confidence: 99%

Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice

et al. 2004

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The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray-based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin-deficient mice, the effects of leptin supplementation on liver regeneration in wildtype mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte-specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor. In conclusion, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration. (HEPATOLOGY 2004;40:1322-1332 T he liver regenerates in response to a variety of injuries. [1][2][3] The rodent partial hepatectomy model has been a useful tool with which to investigate the signals that regulate this regenerative response. Following partial hepatectomy, most of the remaining quiescent hepatocytes in the remnant liver tissue quickly proliferate leading to rapid restoration of appropriate liver mass. 4 Analyses of genetically and pharmacologically manipulated mice using this model have begun to identify the coordinated signaling events that regulate hepatic regeneration. These signals include activation of tumor necrosis factor ␣ (TNF␣) interleukin (IL)-6 signaling, 5-7 generation of mitochondrial reactive oxygen species 8 and prostaglandins 9 , and activation of stress-and mitogenactivated-protein kinase cascades. 10 These signals lead to activation of nuclear factor B (NF B) and other transcription factors, which direct an immediate early gene expression program culminating in growth factor-dependent hepatocellular reentry into and progression through the cell cycle [11][12][13] . Once t...

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“…Other factors are involved in modulating p21 waf1 expression including the transcription factors p150, CEBP␣, and CEBP␤ and altered mRNA and protein stability. 36,39,41,42 Whether the novel ubiquitin ligase and deubiquinating enzymatic activities of A20 are involved in modifying any of these components remains to be determined. 43 Importantly, decreased p21 waf1 mRNA levels and protein expression in livers engineered to express A20, as analyzed by gene chip arrays and immunohistochemistry, is observed prior to liver resection, which suggests that the proliferative advantage provided by A20 to hepatocytes is effective prior to any injury hence is likely independent from the antiapoptotic effect of A20.…”

Section: Discussionmentioning

confidence: 99%

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Longo¹,

Patel²,

Shrikhande³

et al. 2005

Hepatology

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The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-B. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21 waf1 . In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti-inflammatory, antiapoptotic and pro-proliferative functions, A20-based therapies could be beneficial in prevention and treatment of FHF. (HEPATOLOGY 2005;42:156-164.)

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CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy.

Cited by 261 publications

References 57 publications

Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration

Aurora-A Overexpression in Mouse Liver Causes p53-Dependent Premitotic Arrest during Liver Regeneration

Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

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