Non-canonical functions of Cyclin E1 for control of hepatic DNA replication and liver regeneration in mice

2012 ◽  
Vol 50 (01) ◽  
Author(s):  
W Hu ◽  
YA Nevzorova ◽  
U Haas ◽  
P Sicinski ◽  
M Barbacid ◽  
...  
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Cyclin E1

scholarly journals Concurrent deletion of cyclin E1 and cyclin-dependent kinase 2 in hepatocytes inhibits DNA replication and liver regeneration in mice

Hepatology ◽  
2013 ◽  
Vol 59 (2) ◽  
pp. 651-660 ◽  
Author(s):  
Wei Hu ◽  
Yulia A. Nevzorova ◽  
Ute Haas ◽  
Nives Moro ◽  
Piotr Sicinski ◽  
...  
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Cyclin Dependent Kinase ◽  
Cyclin E1

scholarly journals Premature Expression of the Winged Helix Transcription Factor HFH-11B in Regenerating Mouse Liver Accelerates Hepatocyte Entry into S Phase

1999 ◽  
Vol 19 (12) ◽  
pp. 8570-8580 ◽  
Author(s):  
Honggang Ye ◽  
Ai Xuan Holterman ◽  
Kyung W. Yoo ◽  
Roberta R. Franks ◽  
Robert H. Costa
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Nuclear Translocation ◽  
Cyclin B1 ◽  
S Phase ◽  
Hepatocyte Proliferation ◽  
Liver Remnant ◽  
Winged Helix ◽  
Fork Head ◽  
Differentiated Cells

ABSTRACT Two-thirds partial hepatectomy (PH) induces differentiated cells in the liver remnant to proliferate and regenerate to its original size. The proliferation-specific HNF-3/fork head homolog-11B protein (HFH-11B; also known as Trident and Win) is a family member of the winged helix/fork head transcription factors and in regenerating liver its expression is reactivated prior to hepatocyte entry into DNA replication (S phase). To examine whether HFH-11B regulates hepatocyte proliferation during liver regeneration, we used the −3-kb transthyretin (TTR) promoter to create transgenic mice that displayed ectopic hepatocyte expression of HFH-11B. Liver regeneration studies with the TTR–HFH-11B mice demonstrate that its premature expression resulted in an 8-h acceleration in the onset of hepatocyte DNA replication and mitosis. This liver regeneration phenotype is associated with protracted expression of cyclin D1 and C/EBPβ, which are involved in stimulating DNA replication and premature expression of M phase promoting cyclin B1 and cdc2. Consistent with the early hepatocyte entry into S phase, regenerating transgenic livers exhibited earlier expression of DNA repair genes (XRCC1, mHR21spA, and mHR23B). Furthermore, in nonregenerating transgenic livers, ectopic HFH-11B expression did not elicit abnormal hepatocyte proliferation, a finding consistent with the retention of the HFH-11B transgene protein in the cytoplasm. We found that nuclear translocation of the HFH-11B transgene protein requires mitogenic signalling induced by PH and that its premature availability in regenerating transgenic liver allowed nuclear translocation to occur 8 h earlier than in wild type.

scholarly journals Lipid overloading during liver regeneration causes delayed hepatocyte DNA replication by increasing ER stress in mice with simple hepatic steatosis

2013 ◽  
Vol 49 (2) ◽  
pp. 305-316 ◽  
Author(s):  
Mina Hamano ◽  
Hisao Ezaki ◽  
Shinichi Kiso ◽  
Kunimaro Furuta ◽  
Mayumi Egawa ◽  
...  
Keyword(s):  
Dna Replication ◽  
Er Stress ◽  
Liver Regeneration ◽  
Hepatic Steatosis

scholarly journals Both cyclin A and cyclin E have S-phase promoting (SPF) activity in Xenopus egg extracts

1996 ◽  
Vol 109 (6) ◽  
pp. 1555-1563 ◽  
Author(s):  
U.P. Strausfeld ◽  
M. Howell ◽  
P. Descombes ◽  
S. Chevalier ◽  
R.E. Rempel ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cyclin E ◽  
Cyclin A ◽  
Early Embryo ◽  
S Phase ◽  
Chromosomal Dna ◽  
Cyclin E1 ◽  
Egg Extracts ◽  
High Concentrations ◽  
Xenopus Egg Extracts

Extracts of activated Xenopus eggs in which protein synthesis has been inhibited support a single round of chromosomal DNA replication. Affinity-depletion of cyclin dependent kinases (Cdks) from these extracts blocks the initiation of DNA replication. We define ‘S-phase promoting factor’ (SPF) as the Cdk activity required for DNA replication in these Cdk-depleted extracts. Recombinant cyclins A and E, but not cyclin B, showed significant SPF activity. High concentrations of cyclin A promoted entry into mitosis, which inhibited DNA replication. In contrast, high concentrations of cyclin E1 promoted neither nuclear envelope disassembly nor full chromosome condensation. In the early embryo cyclin E1 complexes exclusively with Cdk2 and cyclin A is complexed predominantly with Cdc2; only later in development does cyclin A associate with Cdk2. We show that baculovirus-produced complexes of cyclin A-Cd2, cyclin A-Cdk2 and cyclin E-Cdk2 could each provide SPF activity. These results suggest that although in the early Xenopus embryo cyclin E1-Cdk2 is sufficient to support entry into S-phase, cyclin A-Cdc2 provides a significant additional quantity of SPF as its levels rise during S phase.

scholarly journals Regulation of the G1/S Transition in Hepatocytes: Involvement of the Cyclin-Dependent Kinase Cdk1 in the DNA Replication

2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Anne Corlu ◽  
Pascal Loyer
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Primary Cultures ◽  
G1 Phase ◽  
Cyclin Dependent Kinase ◽  
Restriction Point ◽  
Extracellular Signals ◽  
Combined Use

A singular feature of adult differentiated hepatocytes is their capacity to proliferate allowing liver regeneration. This review emphasizes the literature published over the last 20 years that established the most important pathways regulating the hepatocyte cell cycle. Our article also aimed at illustrating that many discoveries in this field benefited from the combined use ofin vivomodels of liver regeneration andin vitromodels of primary cultures of human and rodent hepatocytes. Using these models, our laboratory has contributed to decipher the different steps of the progression into the G1 phase and the commitment to S phase of proliferating hepatocytes. We identified the mitogen dependent restriction point located at the two-thirds of the G1 phase and the concomitant expression and activation of both Cdk1 and Cdk2 at the G1/S transition. Furthermore, we demonstrated that these two Cdks contribute to the DNA replication. Finally, we provided strong evidences that Cdk1 expression and activation is correlated to extracellular matrix degradation upon stimulation by the pro-inflammatory cytokine TNFαleading to the identification of a new signaling pathway regulating Cdk1 expression at the G1/S transition. It also further confirms the well-orchestrated regulation of liver regeneration via multiple extracellular signals and pathways.

Effect of actinomycin D on DNA replication and c-myc expression during rat liver regeneration

1987 ◽  
Vol 144 (2) ◽  
pp. 1049-1054 ◽  
Author(s):  
Saburo Horikawa ◽  
Keiko Sakata ◽  
Fumiaki Uchiumi ◽  
Masakazu Hatanaka ◽  
Kinji Tsukada
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Rat Liver ◽  
Actinomycin D ◽  
Rat Liver Regeneration

61 CDK2-DEFICIENT HEPATOCYTES REQUIRE NON-CANONICAL FUNCTIONS OF CYCLIN E1 FOR EFFICIENT LIVER REGENERATION IN MICE

2012 ◽  
Vol 56 ◽  
pp. S27
Author(s):  
W. Hu ◽  
Y.A. Nevzorova ◽  
U. Haas ◽  
N. Moro ◽  
P. Sicinski ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Cyclin E1

Temporal expression profiles indicate a primary function for microRNA during the peak of DNA replication after rat partial hepatectomy

2011 ◽  
Vol 300 (6) ◽  
pp. R1363-R1372 ◽  
Author(s):  
Nathanael Raschzok ◽  
Wiebke Werner ◽  
Hannes Sallmon ◽  
Nils Billecke ◽  
Christof Dame ◽  
...  
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Mirna Expression ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Differentially Expressed ◽  
Nuclear Antigen ◽  
Primary Function ◽  
Differentially Expressed Mirnas

The liver has the unique capacity to regenerate after surgical resection. However, the regulation of liver regeneration is not completely understood. Recent reports indicate an essential role for small noncoding microRNAs (miRNAs) in the regulation of hepatic development, carcinogenesis, and early regeneration. We hypothesized that miRNAs are critically involved in all phases of liver regeneration after partial hepatectomy. We performed miRNA microarray analyses after 70% partial hepatectomy in rats under isoflurane anesthesia at different time points (0 h to 5 days) and after sham laparotomy. Putative targets of differentially expressed miRNAs were determined using a bioinformatic approach. Two-dimensional (2D)-PAGE proteomic analyses and protein identification were performed on specimens at 0 and 24 h after resection. The temporal dynamics of liver regeneration were characterized by 5-bromo- 2-deoxyuridine, proliferating cell nuclear antigen, IL-6, and hepatocyte growth factor. We demonstrate that miRNA expression patterns changed during liver regeneration and that these changes were most evident during the peak of DNA replication at 24 h after resection. Expression of 13 miRNAs was significantly reduced 12–48 h after resection (>25% change), out of which downreguation was confirmed in isolated hepatocytes for 6 miRNAs at 24 h, whereas three miRNAs were significantly upregulated. Proteomic analysis revealed 65 upregulated proteins; among them, 23 represent putative targets of the differentially expressed miRNAs. We provide a temporal miRNA expression and proteomic dataset of the regenerating rat liver, which indicates a primary function for miRNA during the peak of DNA replication. These data will assist further functional studies on the role of miRNAs during liver regeneration.

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