Aberrant Cell Cycle Progression and Endoreplication in Regenerating Livers of Mice That Lack a Single E-Type Cyclin

Nevzorova, Yulia A.; Tschaharganeh, Darjus F.; Gaßler, Nikolaus; Geng, Yan; Weiskirchen, Ralf; Siciński, Piotr; Liedtke, Christian

doi:10.1053/j.gastro.2009.05.003

Cited by 60 publications

(76 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure 8, the size of hepatocytes at day 5 after PHx in shEGFR-treated rats seems to be considerably larger than scrambled treated controls. In this context, the down-regulation of Cyclin E1 67 and recruitment of PI3K-Akt pathway by ErbB-3-ErbB-2 heterodimer in shEGFR-treated rats may be significant.…”

Section: Discussionmentioning

confidence: 99%

“…This raises the interesting question in view of suppression of BrdU incorporation: why was no delay in liver regeneration evident? Regeneration of liver (increase in cell mass in absence of cell proliferation) after a PHx has been observed in Skp-2-deficient mice 66 after introduction into hepatocytes of SOC1 and SOC3, both negative regulators of EGFR and MET-mediated STAT3 phosphorylation, 14 in STAT3-deficient mice, 55 in cyclin E2-deleted mice, 67 and in rats and mice subjected to irradiation and to administration of pyrrolizidine alkaloids (such as retrorcine). 68 In all these cases, liver mass was restored by an increase in hepatocyte size.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

Paranjpe

Bowen

Tseng

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Liver regeneration after a two-thirds partial hepatectomy (PHx) is a complex process requiring interaction and cooperation of many growth factors and cytokines and cross talk between multiple pathways. Along with hepatocyte growth factor and its receptor MET (HGF-MET), the epidermal growth factor receptor (EGFR) signaling pathway is activated within 60 minutes after PHx. To investigate the role of EGFR in liver regeneration, we used two EGFR-specific short hairpin silencing RNAs to inhibit EGFR expression in regenerating normal rat liver. Suppression of EGFR mRNA and protein was evident in treated rats. There was also a demonstrable decrease but not complete elimination of bromo-deoxyuridine incorporation and mitoses at 24 hours after PHx. In addition, we observed up-regulation of MET and Src as well as activation of the ErbB-3-ErbB-2-PI3K-Akt pathway and down-regulation of STAT 3, cyclin D1, cyclin E1, p21, and C/EBP ␤. The decrease in the ratio of C/EBP ␣ to C/EBP ␤ known to occur after PHx was offset in shEGFR-treated rats. Despite suppression of hepatocyte proliferation lasting into day 3 after PHx, liver weight restoration occurred. Interestingly, hepatocytes in shEGFR-treated rats were considerably larger when compared with ScrRNA-treated controls. The data indicate that although the MET and EGFR pathways are similar, the contributions made by MET and EGFR are unique and are not compensated by each other or other cytokines. Partial hepatectomy (PHx), in which two thirds of the rat liver is surgically removed, has been extensively used to study the highly complex phenomenon of liver regeneration. Although hepatocytes in normal adult liver are quiescent and rarely divide, they do retain an astounding ability to reenter the cell cycle and regenerate on surgical insult or injury. PHx in rats/mice results in rapid induction of more than 100 genes that are not expressed in the normal resting liver.1 A rapid up-regulation of genes encoding transcriptional factors like AP1 breakdown of extracellular matrix by uPA and release of pre-existing stores of HGF is observed within 60 minutes of a PHx. 2The hepatocytes leave the quiescent G0 phase and enter the cell cycle. Methods to identify extrahepatic signals leading to liver regeneration have included mitogenic effects on hepatocyte cultures, stimulation of DNA synthesis in the liver of normal (unoperated) animals, and decrease in regeneration-related events in animals genetically or pharmacologically depleted of the agent under study. Of the various agents implicated in liver regeneration, HGF and ligands of the epidermal growth factor receptor (EGFR) are the only ones that stimulate DNA synthesis in hepatocyte cultures maintained in chemically defined media.3 They are also the only ones that stimulate DNA synthesis in the liver of normal mice and rats. 4 -6 HGF and EGF signaling pathways are activated within 60 minutes after a PHx, 7,8 as evidenced by tyrosine phosphorylation of MET and EGFR within 30 to 60 minutes after PHx. There is evidence of cross talk and c...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

Paranjpe

Bowen

Tseng

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…20 For example, during liver regeneration, cyclin E1 promotes endoreduplication, while cyclin E2 suppresses it. 21 In addition, cyclin E2 overexpression, but not cyclin E1 overexpression, is associated with shorter survival in some breast cancer subgroups and vice versa. 20,22 Several studies have shown that overexpression of cyclin E1 affects mitotic progression and promotes genomic instability, 7,9,10,23,24 but cyclin E2 has not been studied in this context.…”

Section: Introductionmentioning

confidence: 99%

Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1

et al. 2013

View full text Add to dashboard Cite

“…Mammalian livers have a remarkable capacity for regeneration after partial hepatectomy, and regeneration can occur via Cyclin E-mediated regulation of endoreplication rather than proliferation (Miyaoka et al, 2012;Nevzorova et al, 2009). Because many hepatocytes are normally polyploid, a reasonable hypothesis is that endoreplication is important for normal liver function.…”

Section: Consequences Of Defective Endoreplication During Developmentmentioning

confidence: 99%

Endoreplication and polyploidy: insights into development and disease

2013

View full text Add to dashboard Cite

SummaryPolyploid cells have genomes that contain multiples of the typical diploid chromosome number and are found in many different organisms. Studies in a variety of animal and plant developmental systems have revealed evolutionarily conserved mechanisms that control the generation of polyploidy and have recently begun to provide clues to its physiological function. These studies demonstrate that cellular polyploidy plays important roles during normal development and also contributes to human disease, particularly cancer.Key words: Cancer, Endocycle, Endomitosis, Endoreplication, Genome instability IntroductionPolyploid cells, which contain multiples of the diploid genome equivalent, have been studied for many years, nearly as long as chromosomes themselves have been studied. Now, over a century after the discovery of polyploidy, we know much about the molecular mechanisms that generate cellular polyploidy, but comparably little regarding the physiological function of the polyploid state. This discrepancy exists despite the frequent occurrence of polyploid cells in most multicellular organisms, as well as in human cancers. An important aspect of deciphering the roles for polyploidy lies in understanding the regulation of endoreplication, a cell cycle variation that generates a polyploid genome by repeated rounds of DNA replication in the absence of cell division. Recent advances show that, although some differences exist in the diverse endoreplication programs found from protists to humans, core principles can be applied. New work in genetic model organisms has identified cases in which programmed endoreplication plays key roles in development. Furthermore, recent evidence indicates that endoreplication can confer genome instability, a major cancer-enabling property. In this Primer (see Box), we review such recent discoveries, focusing on work carried out in the past 3 years, and refer the reader to other comprehensive reviews on this topic Lee et al., 2009). From these new insights emerge unifying themes regarding endoreplication that hold promise of elucidating the advantages, as well as the potential disadvantages, of polyploidy. Endoreplication and developmentEndoreplication is typically studied in the context of endopolyploidy, which refers to the presence of polyploid cells in an otherwise diploid organism. Diverse levels of polyploidy occur throughout nature (Table 1). Although polyploidy is well appreciated in plants , many different animal tissues, including the skin, gut, placenta, liver, brain and blood have polyploid cells (Table 1) (Laird et al., 1980;Corash et al., 1989;Fox et al., 2010; Hedgecock and White, 1985;Melaragno et al., 1993;Sherman, 1972;Unhavaithaya and Orr-Weaver, 2012;Zanet et al., 2010). Interestingly, endoreplication is not limited to multi-cellular organisms, with examples described in ciliated protozoa (Yin et al., 2010) and even bacteria (Mendell et al., 2008).Two primary forms of endoreplication have been described: endocycling and endomitosis (Fig. 1). Endocycles are compos...

show abstract

Aberrant Cell Cycle Progression and Endoreplication in Regenerating Livers of Mice That Lack a Single E-Type Cyclin

Cited by 60 publications

References 38 publications

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

RNA Interference Against Hepatic Epidermal Growth Factor Receptor Has Suppressive Effects on Liver Regeneration in Rats

Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1

Endoreplication and polyploidy: insights into development and disease

Contact Info

Product

Resources

About