The Cell Cycle in Polyploid Megakaryocytes Is Associated with Reduced Activity of Cyclin B1-dependent Cdc2 Kinase (*)

The platelet precursor, the megakaryocyte, matures to a polyploid cell as a result of DNA replication in the absence of mitosis (endomitosis). The factors controlling endomitosis are accessible to analysis in our megakaryocytic cell line, MegT, generated by targeted expression of temperature-sensitive simian virus 40 large T antigen to megakaryocytes of transgenic mice. We aimed to define whether endomitosis consists of a continuous phase of DNA synthesis (S) or of S phases interrupted by gaps. Analysis of the cell cycle in MegT cells revealed that, upon inactivation of large T antigen, the cells shifted from a mitotic cell cycle to an endomitotic cell cycle consisting of S/Gap phases. The level of the G/S cyclin, cyclin A, as well as of the G phase cyclin, cyclin D3, were elevated at the onset of DNA synthesis, either in MegT cells undergoing a mitotic cell cycle or during endomitosis. In contrast, the level of the mitotic cyclin, cyclin B1, cycled in cells displaying a mitotic cell cycle while not detectable during endomitosis. Comparable levels of the mitotic kinase protein, Cdc2, were detected during the mitotic cell cycle or during endomitosis; however, cyclin B1-dependent Cdc2 kinase activity was largely abolished in the polyploid cells. Fibroblasts immortalized with the same heat-labile oncogene do not display reduced levels of cyclin B1 upon shifting to high temperature nor do they become polyploid, indicating that reduced levels of cyclin B1 is a property of megakaryocytes and not of the T-antigen mutant. We conclude that cellular programming during endoreduplication in megakaryocytes is associated with reduced levels of cyclin B1.

• Publication year

  1996

• Venue

  Journal of Biological Chemistry

• Publication date

  1996-02-23

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.271.8.4266PMID 8626773
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• The tsA58 simian virus 40 large tumor antigen disrupts megakaryocyte differentiation in transgenic mice.

  1994cited by this paper
• Identification of cut8+ and cek1+, a novel protein kinase gene, which complement a fission yeast mutation that blocks anaphase

  1994cited by this paper
• The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production.

  1994cited by this paper
• Regulation of progression through the Gl phase of the cell cycle by the rum1 + gene

  1994cited by this paper
• c-Mpl ligand is a humoral regulator of megakaryocytopoiesis

  1994cited by this paper
• Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin

  1994cited by this paper
• Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand

  1994cited by this paper
• Mitosis in transition.

  1994cited by this paper
• Premature chromatin condensation upon accumulation of NIMA.

  1994cited by this paper
• The metaphase II arrest in mouse oocytes is controlled through microtubule‐dependent destruction of cyclin B in the presence of CSF.

  1993cited by this paper
• Isolation of the murine cyclin B2 cDNA and characterization of the lineage and temporal specificity of expression of the B1 and B2 cyclins during oogenesis, spermatogenesis and early embryogenesis.

  1993cited by this paper
• Selection of an HEL-derived cell line expressing high levels of platelet factor 4.

  1993cited by this paper
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  1993cited by this paper
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  1993cited by this paper
• Targeted expression of a conditional oncogene in hematopoietic cells of transgenic mice

  1993cited by this paper
• Increment of the cyclin D1 mRNA level in TPA-treated three human myeloid leukemia cell lines: HEL, CMK and HL-60 cells.

  1993cited by this paper
• Altered chromosome 6 in immortal human fibroblasts

  1992cited by this paper
• Identification of a mouse B‐type cyclin which exhibits developmentally regulated expression in the germ line

  1992cited by this paper
• D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA.

  1992cited by this paper
• Retinoblastoma protein and simian virus 40-dependent immortalization of human fibroblasts

  1991cited by this paper
• Platelet factor 4 gene expression in a human megakaryocytic leukemia cell line (CMK) and its differentiated subclone (CMK11-5).

  1991cited by this paper
• Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.

  1991cited by this paper
• The regulation of the cell cycle during Drosophila embryogenesis: the transition to polyteny.

  1991cited by this paper
• Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family.

  1991cited by this paper
• Methylated ubiquitin inhibits cyclin degradation in clam embryo extracts.

  1991cited by this paper
• Uncoupled cell cycle without mitosis induced by a protein kinase inhibitor, K-252a

  1991cited by this paper
• G1-specific cyclins: in search of an S-phase-promoting factor.

  1991cited by this paper
• Yeast as a model system for understanding the control of DNA replication in eukaryotes

  1990cited by this paper
• Human cyclin A is adenovirus E1A-associated protein p60 and behaves differently from cyclin B

  1990cited by this paper
• The roles of Drosophila cyclins A and B in mitotic control.

  1990cited by this paper
• G1-specific cyclins of S. cerevisiae: cell cycle periodicity, regulation by mating pheromone, and association with the p34CDC28 protein kinase.

  1990cited by this paper
• FAR-reaching discoveries about the regulation of START.

  1990cited by this paper
• Checkpoints: controls that ensure the order of cell cycle events.

  1989cited by this paper
• Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF.

  1989cited by this paper
• A family of cyclin homologs that control the G1 phase in yeast.

  1989cited by this paper
• The role of cyclin B in meiosis I

  1989cited by this paper
• The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells

  1989cited by this paper
• Characterization of a new megakaryocytic cell line: the Dami cell.

  1988cited by this paper
• Establishment in long term culture of megakaryocytic leukemia cells (EST-IU) from the marrow of a patient with leukemia and a mediastinal germ cell neoplasm.

  1986cited by this paper
• Myeloid and megakaryocytic properties of K-562 cell lines.

  1983cited by this paper
• Single-cell origin of mouse hemopoietic colonies expressing multiple lineages in variable combinations.

  1983cited by this paper
• Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division.

  1983cited by this paper
• HEL cells: a new human erythroleukemia cell line with spontaneous and induced globin expression.

  1982cited by this paper
• Maturation of the head of bacteriophage T4. I. DNA packaging events.

  1973influential reference
• Generation cycle of rat megakaryocytes

  1968cited by this paper

• Dengue virus modulates critical cell cycle regulatory proteins in human megakaryocyte cells

  2025cites this paper
• Endomitosis: a new cell fate in the cell cycle leading to polyploidy in megakaryocytes and hepatocytes

  2025cites this paper
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  2024cites this paper
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  2022cites this paper
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  2021cites this paper
• Post-Transcriptional Expression Control in Platelet Biogenesis and Function

  2020cites this paper
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  2019cites this paper
• New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors.

  2019cites this paper
• Megakaryocyte Development and Platelet Formation

  2019cites this paper
• Fonctions et régulations de la kinase CHK1 dans l'hématopoïèse normale et leucémique

  2019cites this paper
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  2018cites this paper
• Platelets and Hemostasis

  2018cites this paper
• Megakaryocyte and polyploidization.

  2018cites this paper
• Rôles de la PI3 kinase de classe II alpha et de la PI3K de classe III, vps34, dans la production et les fonctions plaquettaires

  2017cites this paper
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  2017cites this paper
• Progress in bio-manufacture of platelets for transfusion

  2017cites this paper
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  2016cites this paper
• Megakaryopoiesis and Platelet Biogenesis

  2016cites this paper
• Functional reprogramming of polyploidization in megakaryocytes.

  2015cites this paper
• UvA-DARE ( Digital Academic Repository ) Novel regulators of megakaryopoiesis : The road less traveled by Zeddies , S

  2015cites this paper
• Multiple outcomes for PI3K/Akt/mTOR targeting in non-Hodgkin lymphoma

  2015cites this paper
• Etude des mécanismes de formation des plaquettes sanguines : rôle de l'environnement médullaire

  2014cites this paper
• The incredible journey: From megakaryocyte development to platelet formation

  2013cites this paper
• Polyploidy road to therapy‐induced cellular senescence and escape

  2013cites this paper
• Wnt Signaling through the Ror Receptor in the Nervous System

  2013cites this paper
• Overexpression of nuclear distribution protein (hNUDC) causes pro‐apoptosis and differentiation in Dami megakaryocytes

  2013cites this paper
• Kinase (MAPK) Pathway in Normal Megakaryocytes: Role in Endomitosis Thrombopoietin-Induced Activation of the Mitogen-Activated Protein

  2013cites this paper
• deregulated expression - Aurora-B/AIM-1 megakaryocyte polyploidization and the consequences of Aberrant quantity and localization of Aurora-B/AIM-1 and survivin during

  2013cites this paper
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  2013cites this paper
• release cord blood CD34+ cells are correlated with different levels of platelet Different ploidy levels of megakaryocytes generated from peripheral or

  2013cites this paper
• RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

  2012cites this paper
• Hepatocytes Polyploidization and Cell Cycle Control in Liver Physiopathology

  2012cites this paper
• Genetic, molecular, and humoral endocycle-regulating mechanisms

  2011cites this paper
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  2011cites this paper
• Smoothened Signaling Through a G-Protein Effector Network

  2011cites this paper
• Cell Type–dependent Requirement for PIP Box–regulated Cdt1 Destruction During S Phase

  2010cites this paper
• New Roles for Cyclin E in Megakaryocytic Polyploidization*

  2010cites this paper
• Stem cell pluripotency: A cellular trait that depends on transcription factors, chromatin state and a checkpoint deficient cell cycle

  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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  2009cites this paper
• Endoreplication: polyploidy with purpose.

  2009cites this paper
• Development of Megakaryocytes

  2009cites this paper
• Cip/Kip cyclin-dependent protein kinase inhibitors and the road to polyploidy

  2009cites this paper
• Wnt/Frizzled signaling in angiogenesis

  2008cites this paper
• Eternal Youth, the Fate of Developing Arabidopsis Leaves upon Rhodococcus fascians Infection1[C][W][OA]

  2008influential citation
• Expression of Wnt Receptors, Frizzled, in Rat Neuronal Cells

  2008cites this paper
• A casein kinase 2 inhibitor is a potent anti-cancer drug candidate

  2008cites this paper
• Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach.

  2007cites this paper
• Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization.

  2007cites this paper
• APC/C – the master controller of origin licensing?

  2007cites this paper
• Chapter 2 – Megakaryocyte Development and Platelet Formation

  2007cites this paper
• Endomitotic Megakaryocytes form a Midzone in Anaphase but Have a Deficiency in Cleavage Furrow Formation

  2006cites this paper
• Inhibition of TPO-induced MEK or mTOR activity induces opposite effects on the ploidy of human differentiating megakaryocytes

  2006cites this paper
• Mechanism of Aurora-B Degradation and Its Dependency on Intact KEN and A-Boxes: Identification of an Aneuploidy-Promoting Property

  2005cites this paper
• CaSm-mediated cellular transformation is associated with altered gene expression and messenger RNA stability.

  2005cites this paper
• The Evi1 proto‐oncoprotein blocks endomitosis in megakaryocytes by inhibiting sustained cyclin‐dependent kinase 2 catalytic activity

  2005cites this paper
• Stathmin Prevents the Transition from a Normal to an Endomitotic Cell Cycle during Megakaryocytic Differentiation

  2005cites this paper
• Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor

  2004cites this paper
• Aberrant quantity and localization of Aurora-B/AIM-1 and survivin during megakaryocyte polyploidization and the consequences of Aurora-B/AIM-1-deregulated expression.

  2004cites this paper
• Cholesterol is essential for mitosis progression and its deficiency induces polyploid cell formation.

  2004cites this paper
• Production of Polyploid Meth-A Cells Whose Ploidy is not a Power of 2 by Staurosporine

  2004cites this paper
• Megakaryocytes express functional Aurora-B kinase in endomitosis.

  2004cites this paper
• Deregulation of Cdc2 kinase induces caspase-3 activation and apoptosis.

  2003cites this paper
• Human wee1 kinase is directly transactivated by and increased in association with c-Fos/AP-1: rheumatoid synovial cells overexpressing these genes go into aberrant mitosis

  2003cites this paper
• Octaploid Meth‐A cells are established from a highly polyploidized cell population

  2003cites this paper
• Functional activity of NMDA receptors on megakaryocytes

  2003cites this paper
• Megakaryocytes and beyond: the birth of platelets

  2003cites this paper
• E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models.

  2003cites this paper
• An adenosine analogue, IB-MECA, down-regulates estrogen receptor alpha and suppresses human breast cancer cell proliferation.

  2003cites this paper
• Establishment of a triploid V79 cell line from tetraploid cells obtained through polyploidization using K‐252a

  2002cites this paper
• Different ploidy levels of megakaryocytes generated from peripheral or cord blood CD34+ cells are correlated with different levels of platelet release.

  2002cites this paper
• Molecular Control of Megakaryopoiesis and Thrombopoiesis

  2002cites this paper
• Roads to polyploidy: The megakaryocyte example

  2002influential citation
• Polyploidy in murine hepatocytes

  2002cites this paper
• Regulation of the embryonic cell proliferation by Drosophila cyclin D and cyclin E complexes.

  2001cites this paper
• Kinetics of endomitosis in primary murine megakaryocytes

  2001cites this paper
• c‐Fos/activator protein‐1 transactivates wee1 kinase at G1/S to inhibit premature mitosis in antigen‐specific Th1 cells

  2001cites this paper
• Oncoprotein 18 levels and phosphorylation mediate megakaryocyte polyploidization in human erythroleukemia cells

  2001cites this paper
• Downregulation of an Aim-1 Kinase Couples with Megakaryocytic Polyploidization of Human Hematopoietic Cells

  2001cites this paper
• Fluctuation of the ploidy level in the epidermis of Bombyx mori during the penultimate and ultimate larval instars

  2001cites this paper
• Heterologous Expression of the Transcriptional Regulator Escargot Inhibits Megakaryocytic Endomitosis*

  2001cites this paper
• Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system.

  2000cites this paper
• K 562 Cells Resistant to Phorbol 12-Myristate 13-acetate-induced Growth Arrest : Dissociation of Mitogen-activated Protein Kinase Activation and Egr-1 Expression from Megakaryocyte Differentiation 1

  2000cites this paper
• Ectopic expression of cyclin E allows non-endomitotic megakaryoblastic K562 cells to establish re-replication cycles

  2000cites this paper
• The involvement of human-nuc gene in polyploidization of K562 cell line.

  2000cites this paper
• Different responses of polyploidized V79 cells after removal of two drugs, demecolcine and K-252a.

  2000cites this paper
• K562 cells resistant to phorbol 12-myristate 13-acetate-induced growth arrest: dissociation of mitogen-activated protein kinase activation and Egr-1 expression from megakaryocyte differentiation.

  2000cites this paper
• Pneumocystis carinii uses a functional cdc13 B-type cyclin complex during its life cycle.

  2000cites this paper
• Increased D-type Cyclin Expression Together with Decreased cdc2 Activity Confers Megakaryocytic Differentiation of a Human Thrombopoietin-dependent Hematopoietic Cell Line*

  2000cites this paper
• The enigmatic megakaryocyte gradually reveals its secrets.

  1999cites this paper
• The mitotic machinery as a source of genetic instability in cancer.

  1999cites this paper
• Ectopic expression of the Aspergillus nidulans mitotic inducer, nimA kinase, in megakaryocytes: effect on polyploidization.

  1999cites this paper
• Role of a serine/threonine kinase, Mst1, in megakaryocyte differentiation

  1999cites this paper
• Human megakaryocyte ploidy.

  1999cites this paper
• Rat NAP1: cDNA cloning and upregulation by Mpl ligand.

  1999cites this paper
• ERK/MAPK Pathway Is Required for Changes of Cyclin D1 and B1 During Phorbol 12‐Myristate 13‐Acetate‐Induced Differentiation of K562 Cells

  1999cites this paper
• Mpl ligand enhances the transcription of the cyclin D3 gene: a potential role for Sp1 transcription factor.

  1999cites this paper
• Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis.

  1999cites this paper