scholarly journals The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state.

1996 ◽  
Vol 16 (12) ◽  
pp. 6965-6976 ◽  
Author(s):  
E J Smith ◽  
G Leone ◽  
J DeGregori ◽  
L Jakoi ◽  
J R Nevins
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
Kinase Activity ◽  
Transcriptional Repressor ◽  
Negative Control ◽  
Cyclin Dependent Kinase ◽  
Cell State ◽  
Quiescent Cells ◽  
Cycle Dependent ◽  
E2f Proteins

Previous studies have demonstrated cell cycle-dependent specificities in the interactions of E2F proteins with Rb family members. We now show that the formation of an E2F-p130 complex is unique to cells in a quiescent, G0 state. The E2F-p130 complex does not reform when cells reenter a proliferative state and cycle through G1. The presence of an E2F-p130 complex in quiescent cells coincides with the E2F-mediated repression of transcription of the E2F1 gene, and we show that the E2F sites in the E2F1 promoter are important as cells enter quiescence but play no apparent role in cycling cells. In addition, the decay of the E2F-p130 complex as cells reenter the cell cycle requires the action of G1 cyclin-dependent kinase activity. We conclude that the accumulation of the E2F-p130 complex in quiescent cells provides a negative control of certain key target genes and defines a functional distinction between these G0 cells and cells that exist transiently in G1.

scholarly journals Developmental Activation of the Rb–E2F Pathway and Establishment of Cell Cycle-regulated Cyclin-dependent Kinase Activity during Embryonic Stem Cell Differentiation

2005 ◽  
Vol 16 (4) ◽  
pp. 2018-2027 ◽  
Author(s):  
Josephine White ◽  
Elaine Stead ◽  
Renate Faast ◽  
Simon Conn ◽  
Peter Cartwright ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Cyclin Dependent Kinase ◽  
Pluripotent Cells ◽  
Cyclin E1 ◽  
Cdk2 Activity ◽  
Cycle Dependent

To understand cell cycle control mechanisms in early development and how they change during differentiation, we used embryonic stem cells to model embryonic events. Our results demonstrate that as pluripotent cells differentiate, the length of G1 phase increases substantially. At the molecular level, this is associated with a significant change in the size of active cyclin-dependent kinase (Cdk) complexes, the establishment of cell cycle-regulated Cdk2 activity and the activation of a functional Rb–E2F pathway. The switch from constitutive to cell cycle-dependent Cdk2 activity coincides with temporal changes in cyclin A2 and E1 protein levels during the cell cycle. Transcriptional mechanisms underpin the down-regulation of cyclin levels and the establishment of their periodicity during differentiation. As pluripotent cells differentiate and pRb/p107 kinase activities become cell cycle dependent, the E2F–pRb pathway is activated and imposes cell cycle-regulated transcriptional control on E2F target genes, such as cyclin E1. These results suggest the existence of a feedback loop where Cdk2 controls its own activity through regulation of cyclin E1 transcription. Changes in rates of cell division, cell cycle structure and the establishment of cell cycle-regulated Cdk2 activity can therefore be explained by activation of the E2F–pRb pathway.

scholarly journals Phosphoregulation of Rad51/Rad52 by CDK1 functions as a molecular switch for cell cycle–specific activation of homologous recombination

2020 ◽  
Vol 6 (6) ◽  
pp. eaay2669 ◽  
Author(s):  
Gyubum Lim ◽  
Yeonji Chang ◽  
Won-Ki Huh
Keyword(s):  
Cell Cycle ◽  
Homologous Recombination ◽  
Kinase Activity ◽  
Regulatory Mechanism ◽  
Specific Cell ◽  
Cyclin Dependent Kinase ◽  
Recombination Activity ◽  
M Phase ◽  
Dna Binding Affinity ◽  
Cycle Dependent

Homologous recombination is exquisitely activated only during specific cell phases. In the G1 phase, homologous recombination activity is completely suppressed. According to previous reports, the activation of homologous recombination during specific cell phases depends on the kinase activity of cyclin-dependent kinase 1 (CDK1). However, the precise regulatory mechanism and target substrates of CDK1 for this regulation have not been completely determined. Here, we report that the budding yeast CDK1, Cdc28, phosphorylates the major homologous recombination regulators Rad51 and Rad52. This phosphorylation occurs in the G2/M phase by Cdc28 in combination with G2/M phase cyclins. Nonphosphorylatable mutations in Rad51 and Rad52 impair the DNA binding affinity of Rad51 and the affinity between Rad52 rings that leads to their interaction. Collectively, our data provide detailed insights into the regulatory mechanism of cell cycle–dependent homologous recombination activation in eukaryotic cells.

scholarly journals Cyclin-Dependent Kinase Activity Is Required for Progesterone Receptor Function: Novel Role for Cyclin A/Cdk2 as a Progesterone Receptor Coactivator

2005 ◽  
Vol 25 (1) ◽  
pp. 264-277 ◽  
Author(s):  
Ramesh Narayanan ◽  
Abayomi A. Adigun ◽  
Dean P. Edwards ◽  
Nancy L. Weigel
Keyword(s):  
Cell Cycle ◽  
Progesterone Receptor ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Kinase Activity ◽  
Cyclin A ◽  
Cyclin Dependent Kinase ◽  
Histone H4 Acetylation ◽  
Target Promoter

ABSTRACT Our studies examining the role of the cell cycle-regulated kinase cyclin A/Cdk2 in progesterone receptor (PR) action have demonstrated that cyclin-dependent kinase activity is required for PR function and that cyclin A/Cdk2 functions as a PR coactivator. Although Cdk2 can phosphorylate PR, elimination of these phosphorylation sites has little effect on the ability of cyclin A/Cdk2 to stimulate PR activity. PR interacts with cyclin A and recruits cyclin A/Cdk2 to progestin-responsive promoters, stimulating transcription. Inhibition of Cdk2 activity abolishes progesterone-dependent activation of PR target genes in part through inhibition of PR-dependent recruitment of steroid receptor coactivator 1 (SRC-1) and subsequent histone H4 acetylation at the target promoter. In vitro studies revealed that the interaction between SRC-1 and PR is dependent upon phosphorylation of SRC-1. This heretofore-unknown mechanism provides a potential means for integrating the regulation of PR activity with cell cycle progression. Moreover, the ability of PR to recruit cyclin A/Cdk2 to target promoters provides locally elevated levels of kinase, which can preferentially facilitate phosphorylation-dependent interactions and enzymatic activities of coactivators at the target promoter.

scholarly journals Cdk1 promotes cytokinesis in fission yeast through activation of the septation initiation network

2014 ◽  
Vol 25 (15) ◽  
pp. 2250-2259 ◽  
Author(s):  
Nicole Rachfall ◽  
Alyssa E. Johnson ◽  
Sapna Mehta ◽  
Jun-Song Chen ◽  
Kathleen L. Gould
Keyword(s):  
Cell Cycle ◽  
Spindle Pole Body ◽  
Complete Removal ◽  
Spindle Pole ◽  
Cyclin Dependent Kinase ◽  
Gtpase Activating Protein ◽  
Pole Body ◽  
Kinase Cascade ◽  
Septation Initiation Network ◽  
Cycle Dependent

In Schizosaccharomyces pombe, late mitotic events are coordinated with cytokinesis by the septation initiation network (SIN), an essential spindle pole body (SPB)–associated kinase cascade, which controls the formation, maintenance, and constriction of the cytokinetic ring. It is not fully understood how SIN initiation is temporally regulated, but it depends on the activation of the GTPase Spg1, which is inhibited during interphase by the essential bipartite GTPase-activating protein Byr4-Cdc16. Cells are particularly sensitive to the modulation of Byr4, which undergoes cell cycle–dependent phosphorylation presumed to regulate its function. Polo-like kinase, which promotes SIN activation, is partially responsible for Byr4 phosphorylation. Here we show that Byr4 is also controlled by cyclin-dependent kinase (Cdk1)–mediated phosphorylation. A Cdk1 nonphosphorylatable Byr4 phosphomutant displays severe cell division defects, including the formation of elongated, multinucleate cells, failure to maintain the cytokinetic ring, and compromised SPB association of the SIN kinase Cdc7. Our analyses show that Cdk1-mediated phosphoregulation of Byr4 facilitates complete removal of Byr4 from metaphase SPBs in concert with Plo1, revealing an unexpected role for Cdk1 in promoting cytokinesis through activation of the SIN pathway.

Induction of UGT1A1 and CYP2B6 by an Antimitogenic Factor in HepG2 Cells Is Mediated through Suppression of Cyclin-Dependent Kinase 2 Activity: Cell Cycle-Dependent Expression

2009 ◽  
Vol 38 (1) ◽  
pp. 177-186 ◽  
Author(s):  
Junko Sugatani ◽  
Makoto Osabe ◽  
Masatoshi Kurosawa ◽  
Naomi Kitamura ◽  
Akira Ikari ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Hepg2 Cells ◽  
Cyclin Dependent Kinase ◽  
Cycle Dependent

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 Biochemical analyses reveal amino acid residues critical for cell cycle-dependent phosphorylation of human Cdc14A phosphatase by cyclin-dependent kinase 1

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Sara Ovejero ◽  
Patricia Ayala ◽  
Marcos Malumbres ◽  
Felipe X. Pimentel-Muiños ◽  
Avelino Bueno ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Amino Acid Residues ◽  
Cyclin Dependent Kinase ◽  
Biochemical Analyses ◽  
Cycle Dependent

Flavopiridol Down-Regulates Genes Involved in Cell Cycle Regulation and Tumor Progression in Adults with Refractory or Poor-Risk Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 953-953 ◽  
Author(s):  
Linda Resar ◽  
Joelle Hillion ◽  
Katrina Alino ◽  
Michelle Rudek ◽  
Judith Karp
Keyword(s):  
Cell Cycle ◽  
Acute Leukemia ◽  
Rna Polymerase ◽  
Cyclin D1 ◽  
Rna Polymerase Ii ◽  
Target Genes ◽  
Mrna Levels ◽  
Cyclin Dependent Kinase ◽  
Poor Risk ◽  
Before And After

Abstract Acute leukemia in adults continues to be a formidable clinical challenge that demands further investigation to identify more rational therapies. To optimize anti-leukemia therapy, we are investigating the prototypical cyclin dependent kinase (cdk) inhibitor, flavopiridol, in refractory or poor-risk disease. Flavopiridol is a cytotoxic molecule that is thought to induce cell cycle arrest by blocking cyclin-dependent kinase (cdk) function, thereby interfering with RNA Polymerase II activity and globally down-regulating gene expression. In the setting of pan-cdk inhibition, E2F1 is released and appears to drive apoptosis in transformed cells. Consistent with these proposed mechanisms of action, a previous study from our group showed that flavopiridol induces apoptosis in vitro in leukemic blasts from patients with refractory leukemia. Administration of flavopiridol was associated with a decrease in one or more of the following proteins in the leukemic blasts: RNA Polymerase II, STAT3, cyclin D1, Bcl-2, and Mcl-1. Serum VEGF levels also decreased in most patients. We are now investigating mRNA levels of the genes encoding these proteins by quantitative, RT-PCR in leukemic blasts from adult patients with refractory or poor-risk leukemia before and after flavopiridol therapy. We have treated 26 patients with flavopiridol at an escalating, hybrid dose followed by ara-c and mitxantrone. Adequate RNA from leukemic blasts before and after flavopiridol administration was available from 8 of 11 patients studied thus far. All cases (8/8) exhibit a marked decrease in mRNA for VEGF following flavopiridol. mRNA levels for other putative flavopiridol target genes is also decreased in a subset of leukemic blast samples after therapy, as follows: E2F1 (6/8), STAT3 (6/8), Mcl-1 (6/8), RNA Polymerase subunit 2a (3/3), and cyclin D1 (2/3). In contrast, bcl-2 mRNA levels increased after flavopiridol in most cases (7/8), which could represent a compensatory mechanism of leukemic blasts to avoid apoptotic cell death. Our preliminary studies indicate that flavopiridol is cytotoxic in poor-risk and refractory acute leukemia. Studies are underway to determine if down-regulation of any putative target genes correlates with pharmacologic data or clinical responses.

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