title: A role for cyclin D3 in the endomitotic cell cycle.
abstract: Platelets, essential for thrombosis and hemostasis, develop from polyploid megakaryocytes which undergo endomitosis. During this cell cycle, cells experience abrogated mitosis and reenter a phase of DNA synthesis, thus leading to endomitosis. In the search for regulators of the endomitotic cell cycle, we have identified cyclin D3 as an important regulatory factor. Of the D-type cyclins, cyclin D3 is present at high levels in megakaryocytes undergoing endomitosis and is markedly upregulated following exposure to the proliferation-, maturation-, and ploidy-promoting factor, Mpl ligand. Transgenic mice in which cyclin D3 is overexpressed in the platelet lineage display a striking increase in endomitosis, similar to changes seen following Mpl ligand administration to normal mice. Electron microscopy analysis revealed that unlike such treated mice, however, D3 transgenic mice show a poor development of demarcation membranes, from which platelets are believed to fragment, and no increase in platelets. Thus, while our model supports a key role for cyclin D3 in the endomitotic cell cycle, it also points to the unique role of Mpl ligand in priming megakaryocytes towards platelet fragmentation. The role of cyclin D3 in promoting endomitosis in other lineages programmed to abrogate mitosis will need further exploration.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Zimmet
authors.forename: D
authors.initials: D
authors.lastname: Ladd
authors.forename: C W
authors.initials: CW
authors.lastname: Jackson
authors.forename: P E
authors.initials: PE
authors.lastname: Stenberg
authors.forename: K
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D010978:Platelet Factor 4 / Q000235:genetics; D011092:Polyethylene Glycols / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013926:Thrombopoietin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C534696:CCND3 protein, human; C534697:Ccnd3 protein, mouse; D056743:Cyclin D3; D016213:Cyclins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D010978:Platelet Factor 4; D011092:Polyethylene Glycols; D004247:DNA; D013926:Thrombopoietin