title: Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation.
abstract: Physiological polyploidy is a characteristic of several cell types including the megakaryocytes (MK) that give rise to circulating blood platelets. MK achieve polyploidy by switching from a normal to an endomitotic cell cycle characterized by the absence of late mitotic stages. During an endomitotic cycle, the cells enter into mitosis and proceed normally through metaphase and early anaphase. However, late anaphase, telophase and cytokinesis are aborted. This abortive mitosis is associated with atypical multipolar mitotic spindles and limited chromosome segregation. Stathmin is a microtubule-depolymerizing protein that is important for the regulation of the mitotic spindle and interfering with its expression disrupts the normal mitotic spindle and leads to aberrant mitotic exit. As cells enter mitosis, the microtubule depolymerizing-activity of stathmin is switched-off, allowing microtubules to polymerize and assemble into a mitotic spindle. Reactivation of stathmin in the later stages of mitosis is necessary for the disassembly of the mitotic spindle and the exit from mitosis. Previous studies had shown that stathmin expression is downregulated as MK become polyploid and inhibition of its expression in K562 cells increases their propensity to become polyploid. In this report, we describe our studies of the mechanism by which stathmin plays its role in MK polyploidization. We show that stathmin overexpression prevents the transition from a mitotic cycle to an endomitotic cycle as determined by a decrease in the number of multipolar mitotic spindles. These observations support a model in which downregulation of stathmin expression in megakaryocytes and other polyploid cells may be a critically important factor in endomitosis and polyploidy.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Camelia
authors.initials: C
authors.lastname: Iancu-Rubin
authors.forename: Chris A
authors.initials: CA
authors.lastname: Nasrallah
authors.forename: George F
authors.initials: GF
authors.lastname: Atweh
mesh_terms: D002454:Cell Differentiation; D015870:Gene Expression; D006801:Humans; D020014:K562 Cells; D008533:Megakaryocytes / Q000166:cytology*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D011123:Polyploidy; D008941:Spindle Apparatus / Q000187:drug effects; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013752:Tetracycline / Q000378:metabolism
chemical_list: D050777:Stathmin; D013752:Tetracycline; D019311:Staurosporine