Downregulation of an Aim-1 Kinase Couples with Megakaryocytic Polyploidization of Human Hematopoietic Cells

Kawasaki, Akira; Matsumura, Itaru; Miyagawa, Jun Ichiro; Ezoe, Sachiko; Tanaka, Hirokazu; Terada, Yasuhiko; Tatsuka, Masaaki; Machii, Takashi; Miyazaki, Hiroshi; Furukawa, Yusuke; Kanakura, Yuzuru

doi:10.1083/jcb.152.2.275

Cited by 56 publications

(64 citation statements)

References 48 publications

(69 reference statements)

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“…Aurora-B/AIM-1 was shown to be downregulated during polyploidization in MK, and its overexpression prevented chemically-induced polyploidization in megakaryocytic cell lines. 7 Zhang et al confirmed these observations by showing that Aurora-B/AIM-1 is either absent or mislocalized in murine MK. 8 In addition, this study demonstrated that survivin, another chromosomal passenger protein, is absent during the endomitotic cell cycle.…”

Section: Introductionsupporting

confidence: 67%

Stathmin Prevents the Transition from a Normal to an Endomitotic Cell Cycle during Megakaryocytic Differentiation

Iancu‐Rubin

Nasrallah²,

Atweh³

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2171 KEY WORDS ACKNOWLEDGEMENTSThis work was supported in part by grants from the National Institute of Health (HL073438) and the Department of Defense (PC030898) to GFA. Microscopy was performed at the MSSMMicroscopy Shared Resource Facility, supported, in part, with funding from NIH-NCI shared resources grant (R24 CA095823). Report Stathmin Prevents the Transition from a Normal to an Endomitotic Cell Cycle during Megakaryocytic Differentiation ABSTRACTPhysiological 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.

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Section: Introductionsupporting

confidence: 67%

Stathmin Prevents the Transition from a Normal to an Endomitotic Cell Cycle during Megakaryocytic Differentiation

Iancu‐Rubin

Nasrallah²,

Atweh³

2005

Cell Cycle

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“…The mechanism of the switch from mitosis to endomitosis in MK is still a matter of controversy [26][27][28][29][30] with studies suggesting a cell cycle regulation defect, whereas others argue for a defect in the expression of the central spindle proteins. Our new findings demonstrate the key contribution of MYH10 downregulation in the process of the switch from mitosis to endomitosis.…”

Section: Discussionmentioning

confidence: 99%

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

et al. 2012

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megakaryocytes are unique mammalian cells that undergo polyploidization (endomitosis) during differentiation, leading to an increase in cell size and protein production that precedes platelet production. Recent evidence demonstrates that endomitosis is a consequence of a late failure in cytokinesis associated with a contractile ring defect. Here we show that the non-muscle myosin IIB heavy chain (mYH10) is expressed in immature megakaryocytes and specifically localizes in the contractile ring. mYH10 downmodulation by short hairpin RnA increases polyploidization by inhibiting the return of 4n cells to 2n, but other regulators, such as of the G1/s transition, might regulate further polyploidization of the 4n cells. Conversely, re-expression of mYH10 in the megakaryocytes prevents polyploidization and the transition of 2n to 4n cells. During polyploidization, mYH10 expression is repressed by the major megakaryocyte transcription factor RunX1. Thus, RunX1-mediated silencing of mYH10 is required for the switch from mitosis to endomitosis, linking polyploidization with megakaryocyte differentiation.

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“…Although it is expressed in murine megakaryocytes during prophase, it is absent or mislocalized during late anaphase, when Aurora B and survivin usually become localized to the midzone in dividing cells (22). Interestingly, overexpression of Aurora B in cell lines treated with phorbol esters prevented polyploidization (26) and transgenic mice that overexpress Aurora B in megakaryocytes show evidence of abnormal maturation, with an enhanced number of megakaryocytes with increased proliferative potential and, in some cases, a mild decrease in ploidy level (22). These findings support the conclusion that Aurora B needs to be degraded, or mislocalized, at late stages of the endomitotic cell cycle in megakaryocytes.…”

Section: Discussionmentioning

confidence: 99%

Differential requirements for survivin in hematopoietic cell development

Gurbuxani

Keerthivasan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Although erythroid cells and megakaryocytes arise from a common progenitor, their terminal maturation follows very different paths; erythroid cells undergo cell-cycle exit and enucleation, whereas megakaryocytes continue to progress through the cell cycle but skip late stages of mitosis to become polyploid cells. In our efforts to identify genes that participate in this process, we discovered that survivin, a member of the inhibitor of apoptosis family that also has an essential role in cytokinesis, is differentially expressed during erythroid versus megakaryocyte development. Erythroid cells express survivin throughout their maturation, whereas megakaryocytes express Ϸ4-fold lower levels of survivin mRNA and no detectable protein. To investigate the role of survivin in these lineages, we overexpressed or knocked down survivin from mouse bone marrow cells and then examined erythroid and megakaryocyte development. These studies revealed that overexpression of survivin antagonized megakaryocyte growth, maturation, and polyploidization but had no effect on erythroid development. This block in polyploidization was accompanied by increased expression of p21 and decreased expression of megakaryocyte genes such as von Willebrand factor and ␤1-tubulin. In contrast, a reduction in survivin expression interfered with the formation of erythroid cells but not megakaryocytes. Last, consistent with the requirement for survivin in the survival of proliferating cells, survivin-deficient hematopoietic progenitors failed to give rise to either erythroid or megakaryocytic colonies. Together, these studies show that whereas survivin expression is essential for megakaryocyte and erythroid progenitors, its down-regulation is required for terminal differentiation of megakaryocytes.erythropoiesis ͉ hematopoiesis ͉ megakaryopoiesis

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Downregulation of an Aim-1 Kinase Couples with Megakaryocytic Polyploidization of Human Hematopoietic Cells

Cited by 56 publications

References 48 publications

Stathmin Prevents the Transition from a Normal to an Endomitotic Cell Cycle during Megakaryocytic Differentiation

Stathmin Prevents the Transition from a Normal to an Endomitotic Cell Cycle during Megakaryocytic Differentiation

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

Differential requirements for survivin in hematopoietic cell development

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