Faculty Opinions recommendation of Concurrent deletion of cyclin E1 and cyclin-dependent kinase 2 in hepatocytes inhibits DNA replication and liver regeneration in mice.

2013 ◽  
Author(s):  
Philipp Kaldis
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Cyclin Dependent Kinase ◽  
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

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 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.

Cyclin-dependent kinase 1 plays a critical role in DNA replication control during rat liver regeneration

Hepatology ◽  
2009 ◽  
Vol 50 (6) ◽  
pp. 1946-1956 ◽  
Author(s):  
Delphine Garnier ◽  
Pascal Loyer ◽  
Catherine Ribault ◽  
Christiane Guguen-Guillouzo ◽  
Anne Corlu
Keyword(s):  
Dna Replication ◽  
Liver Regeneration ◽  
Rat Liver ◽  
Critical Role ◽  
Cyclin Dependent Kinase ◽  
Rat Liver Regeneration ◽  
Replication Control

scholarly journals Regulation of Replication Licensing by Acetyltransferase Hbo1

2006 ◽  
Vol 26 (3) ◽  
pp. 1098-1108 ◽  
Author(s):  
Masayoshi Iizuka ◽  
Tomoko Matsui ◽  
Haruhiko Takisawa ◽  
M. Mitchell Smith
Keyword(s):  
Dna Replication ◽  
Origin Recognition Complex ◽  
Cyclin Dependent Kinase ◽  
Chromatin Binding ◽  
Regulatory Factor ◽  
Minichromosome Maintenance ◽  
Egg Extracts ◽  
Sequential Binding ◽  
Initiation Of Dna Replication ◽  
Prereplicative Complex

ABSTRACT The initiation of DNA replication is tightly regulated in eukaryotic cells to ensure that the genome is precisely duplicated once and only once per cell cycle. This is accomplished by controlling the assembly of a prereplicative complex (pre-RC) which involves the sequential binding to replication origins of the origin recognition complex (ORC), Cdc6/Cdc18, Cdt1, and the minichromosome maintenance complex (Mcm2-Mcm7, or Mcm2-7). Several mechanisms of pre-RC regulation are known, including ATP utilization, cyclin-dependent kinase levels, protein turnover, and Cdt1 binding by geminin. Histone acetylation may also affect the initiation of DNA replication, but at present neither the enzymes nor the steps involved are known. Here, we show that Hbo1, a member of the MYST histone acetyltransferase family, is a previously unrecognized positive regulatory factor for pre-RC assembly. When Hbo1 expression was inhibited in human cells, Mcm2-7 failed to associate with chromatin even though ORC and Cdc6 loading was normal. When Xenopus egg extracts were immunodepleted of Xenopus Hbo1 (XHbo1), chromatin binding of Mcm2-7 was lost, and DNA replication was abolished. The binding of Mcm2-7 to chromatin in XHbo1-depleted extracts could be restored by the addition of recombinant Cdt1.

scholarly journals Computational modelling of chromosome re-replication in mutant strains of fission yeast

2020 ◽  
Author(s):  
Béla Novák ◽  
John J Tyson
Keyword(s):  
Dna Replication ◽  
Fission Yeast ◽  
Computational Modelling ◽  
Mitotic Cell ◽  
Cyclin Dependent Kinase ◽  
Slow Increase ◽  
Cell Cycles ◽  
Mitotic Cyclin ◽  
The Mathematical Model ◽  
Insight Into

AbstractTypically cells replicate their genome only once per division cycle, but under some circumstances, both natural and unnatural, cells synthesize an overabundance of DNA, either in a disorganized fashion (‘over-replication’) or by a systematic doubling of chromosome number (‘endoreplication’). These variations on the theme of DNA replication and division have been studied in strains of fission yeast, Schizosaccharomyces pombe, carrying mutations that interfere with the function of mitotic cyclin-dependent kinase (Cdk1:Cdc13) without impeding the roles of DNA-replication licensing factor (Cdc18) and S-phase cyclin-dependent kinase (Cdk1:Cig2). Some of these mutations support endoreplication, and some over-replication. In this paper, we propose a dynamical model of the interactions among the proteins governing DNA replication and cell division in fission yeast. By computational simulations of the mathematical model, we account for the observed phenotypes of these re-replicating mutants, and by theoretical analysis of the dynamical system, we provide insight into the molecular distinctions between over-replicating and endoreplicating cells. In case of induced over-production of regulatory proteins, our model predicts that cells first switch from normal mitotic cell cycles to growth-controlled endoreplication, and ultimately to disorganized over-replication, parallel to the slow increase of protein to very high levels.

scholarly journals Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma

2018 ◽  
Vol 115 (37) ◽  
pp. 9282-9287 ◽  
Author(s):  
Roland Sonntag ◽  
Nives Giebeler ◽  
Yulia A. Nevzorova ◽  
Jörg-Martin Bangen ◽  
Dirk Fahrenkamp ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Gene Signature ◽  
Cyclin Dependent Kinase ◽  
Regulatory Subunits ◽  
Cyclin E1 ◽  
Quiescent Cells ◽  
Similar Expression Profile ◽  
Regulation Of Cell Cycle

E-type cyclins E1 (CcnE1) and E2 (CcnE2) are regulatory subunits of cyclin-dependent kinase 2 (Cdk2) and thought to control the transition of quiescent cells into the cell cycle. Initial findings indicated that CcnE1 and CcnE2 have largely overlapping functions for cancer development in several tumor entities including hepatocellular carcinoma (HCC). In the present study, we dissected the differential contributions of CcnE1, CcnE2, and Cdk2 for initiation and progression of HCC in mice and patients. To this end, we tested the HCC susceptibility in mice with constitutive deficiency for CcnE1 or CcnE2 as well as in mice lacking Cdk2 in hepatocytes. Genetic inactivation of CcnE1 largely prevented development of liver cancer in mice in two established HCC models, while ablation of CcnE2 had no effect on hepatocarcinogenesis. Importantly, CcnE1-driven HCC initiation was dependent on Cdk2. However, isolated primary hepatoma cells typically acquired independence on CcnE1 and Cdk2 with increasing progression in vitro, which was associated with a gene signature involving secondary induction of CcnE2 and up-regulation of cell cycle and DNA repair pathways. Importantly, a similar expression profile was also found in HCC patients with elevated CcnE2 expression and poor survival. In general, overall survival in HCC patients was synergistically affected by expression of CcnE1 and CcnE2, but not through Cdk2. Our study suggests that HCC initiation specifically depends on CcnE1 and Cdk2, while HCC progression requires expression of any E-cyclin, but no Cdk2.

scholarly journals The proteasome controls ESCRT-III–mediated cell division in an archaeon

Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. eaaz2532 ◽  
Author(s):  
Gabriel Tarrason Risa ◽  
Fredrik Hurtig ◽  
Sian Bray ◽  
Anne E. Hafner ◽  
Lena Harker-Kirschneck ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Dna Replication ◽  
Division Ring ◽  
Cell Cycle Control ◽  
Sulfolobus Acidocaldarius ◽  
Cyclin Dependent Kinase ◽  
Membrane Remodeling

Sulfolobus acidocaldarius is the closest experimentally tractable archaeal relative of eukaryotes and, despite lacking obvious cyclin-dependent kinase and cyclin homologs, has an ordered eukaryote-like cell cycle with distinct phases of DNA replication and division. Here, in exploring the mechanism of cell division in S. acidocaldarius, we identify a role for the archaeal proteasome in regulating the transition from the end of one cell cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome and show that its degradation triggers division by allowing constriction of the CdvB1:CdvB2 ESCRT-III division ring. These findings offer a minimal mechanism for ESCRT-III–mediated membrane remodeling and point to a conserved role for the proteasome in eukaryotic and archaeal cell cycle control.

scholarly journals Periodic Expression of the Cyclin-dependent Kinase Inhibitor p57Kip2 in Trophoblast Giant Cells Defines a G2-like Gap Phase of the Endocycle

2000 ◽  
Vol 11 (3) ◽  
pp. 1037-1045 ◽  
Author(s):  
Naka Hattori ◽  
Tyler C. Davies ◽  
Lynn Anson-Cartwright ◽  
James C. Cross
Keyword(s):  
Dna Replication ◽  
Protein Targeting ◽  
Kinase Inhibitor ◽  
Phosphorylation Site ◽  
Giant Cells ◽  
S Phase ◽  
Stable Form ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Trophoblast Giant Cells

Endoreduplication is an unusual form of cell cycle in which rounds of DNA synthesis repeat in the absence of intervening mitoses. How G1/S cyclin-dependent kinase (Cdk) activity is regulated during the mammalian endocycle is poorly understood. We show here that expression of the G1/S Cdk inhibitor p57Kip2 is induced coincidentally with the transition to the endocycle in trophoblast giant cells.Kip2 mRNA is constitutively expressed during subsequent endocycles, but the protein level fluctuates. In trophoblast giant cells synchronized for the first few endocycles, the p57Kip2 protein accumulates only at the end of S-phase and then rapidly disappears a few hours before the onset of the next S-phase. The protein becomes stabilized by mutation of a C-terminal Cdk phosphorylation site. As a consequence, introduction of this stable form of p57Kip2 into giant cells blocks S-phase entry. These data imply that p57Kip2 is subject to phosphorylation-dependent turnover. Surprisingly, although this occurs in endoreduplicating giant cells, p57Kip2 is stable when ectopically expressed in proliferating trophoblast cells, indicating that these cells lack the mechanism for protein targeting and/or degradation. These data show that the appearance of p57Kip2punctuates the completion of DNA replication, whereas its turnover is subsequently required to initiate the next round of endoreduplication in trophoblast giant cells. Cyclical expression of a Cdk inhibitor, by terminating G1/S Cdk activity, may help promote the resetting of DNA replication machinery.

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