Human AIM-1: cDNA cloning and reduced expression during endomitosis in megakaryocyte-lineage cells

Katayama, Hiroshi; Ota, Takayo; Morita, Kenji; Terada, Yasuhiko; Suzuki, Fumio; Katoh, Osamu; Tatsuka, Masaaki

doi:10.1016/s0378-1119(98)00522-8

Cited by 21 publications

(20 citation statements)

References 31 publications

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“…Our data are in contrast to recent studies [12][13][14] in which it was concluded that Aurora-B kinase is either deficient or absent in polyploidizing megakaryocytic cell lines or in MKs. There are several possible explanations for the discrepant findings between our data and these reports.…”

Section: Discussioncontrasting

confidence: 99%

“…[2][3][4][5][6][7][8][9][10][11] Recently, several reports have suggested that the failure of normal cytokinesis in EnM MKs involves the deficiency of a mitotic kinase, Aurora-B kinase. [12][13][14] The family of aurora kinases now includes many described members in several species, and for simplicity they can be grouped according to their primary localization and function into type A, type B, and type C (for reviews, see Adams et al 15 and Giet and Prigent 16 ). Aurora-A kinase (also known as IAK1) localizes to the centrosome at the mitotic spindle pole and is proposed to function in late anaphase, promoting spindle elongation and centrosome separation.…”

Section: Introductionmentioning

confidence: 99%

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Megakaryocytes express functional Aurora-B kinase in endomitosis

Geddis

Kaushansky

2004

Blood

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Endomitosis (EnM) in megakaryocytes (MKs) is characterized by abortion of mitosis in late anaphase and failure of cytokinesis; subsequent reinitiation of DNA synthesis results in polyploidy. Ablation of chromosomal passenger proteins including Aurora-B kinase causes defects in late anaphase and cytokinesis in diploid cells; thus one hypothesis is that the expression or function of these proteins in polyploid MKs is abnormal. It has been reported that Aurora-B kinase mRNA is decreased in polyploid megakaryocytic cells, suggesting that deficiency of Aurora-B kinase is responsible for EnM. We examined the localization of Aurora-B kinase and additional members of the chromosomal passenger protein and aurora kinase families in MKs. We found that in EnM MKs (1) Aurora-B kinase is present and appropriately localized to centromeres in early EnM; (2)

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Megakaryocytes express functional Aurora-B kinase in endomitosis

Geddis

Kaushansky

2004

Blood

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“…As Aurora-B is a mitotic kinase, it is conceivable that Aurora-B might be regulated throughout the cell cycle at different levels, including at mRNA and protein levels, as shown in megakaryocytic and other cell lines (21,22), and/or at enzyme activity level (42). Mitotic regulators are typically degraded via the ubiquitin-proteasome pathway and APC/c.…”

Section: Discussionmentioning

confidence: 99%

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

Nguyen

Chinnappan

Urano

et al. 2005

Molecular and Cellular Biology

139

145

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The kinase Aurora-B, a regulator of chromosome segregation and cytokinesis, is highly expressed in a variety of tumors. During the cell cycle, the level of this protein is tightly controlled, and its deregulated abundance is suspected to contribute to aneuploidy. Here, we provide evidence that Aurora-B is a short-lived protein degraded by the proteasome via the anaphase-promoting cyclosome complex (APC/c) pathway. Aurora-B interacts with the APC/c through the Cdc27 subunit, Aurora-B is ubiquitinated, and its level is increased upon treatment with inhibitors of the proteasome. Aurora-B binds in vivo to the degradation-targeting proteins Cdh1 and Cdc20, the overexpression of which accelerates Aurora-B degradation. Using deletions or point mutations of the five putative degradation signals in Aurora-B, we show that degradation of this protein does not depend on its D-boxes (RXXL), but it does require intact KEN boxes and A-boxes (QRVL) located within the first 65 amino acids. Cells transfected with wild-type or A-box-mutated or KEN box-mutated Aurora-B fused to green fluorescent protein display the protein localized to the chromosomes and then to the midzone during mitosis, but the mutated forms are detected at greater intensities. Hence, we identified the degradation pathway for Aurora-B as well as critical regions for its clearance. Intriguingly, overexpression of a stable form of Aurora-B alone induces aneuploidy and anchorage-independent growth.

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“…36,44 In favor of this hypothesis, the aurora kinase AIM1 has been shown to be down-regulated in the megakaryocyte. 45 Finally, a defect of C kinesin degradation might also compromise the anaphase B process in megakaryocytes.All these hypotheses have to be confirmed in the future with the help of other eukaryote cell models. …”

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confidence: 99%

Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes

Roy

Coullin

Vitrat

et al. 2001

Blood

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During differentiation, megakaryocytes increase ploidy through a process called endomitosis, whose mechanisms remain unknown. As it corresponds to abortive mitosis at anaphase and is associated with a multipolar spindle, investigation of chromosome segregation may help to better understand this cell-cycle abnormality. To examine this variation, a new method was developed to combine primed in situ labeling to label centromeres of one chromosome category and immunostaining of tubulin. Human megakaryocytes were obtained from normal bone marrow culture. By confocal microscopy, this study demonstrates an asymmetrical distribution of chromosomes (1 or 7) either between the spindle poles at anaphase stage of endomitosis and between the different lobes of interphase megakaryocyte nuclei. The metaphase/ anaphase checkpoint appears normal on the evidence that under nocodazole treatment megakaryocytes progressively accumulate in pseudo-metaphase, without spontaneous escape from this blockage. Immunostaining of p55CDC/hCDC20 with similar kinetochore localization and dynamics as during normal mitosis confirms this result. HCdh1 was also expressed in megakaryocytes, and its main target, cyclin B1, was normally degraded at anaphase, suggesting that the hCdh1-anaphase-promoting complex checkpoint was also functional. This study found the explanation for these unexpected results of an asymmetrical segregation coupled to normal checkpoints by careful analysis of multipolar endomitotic spindles: whereas each aster is connected to more than one other aster, one chromosome may segregate symmetrically between 2 spindle poles and still show asymmetrical segregation when the entire complex spindle is considered. IntroductionMegakaryocytes are polyploid cells that increase their DNA content through an original process called endomitosis. 1 Megakaryocyte progenitors proliferate through normal 2N to 4N cycles under hematopoietic growth factor control. They begin terminal differentiation with synthesis of specific platelet proteins (promegakaryoblast stage), followed by a switch from a mitotic to an endomitotic process, which is characterized by a complete DNA replication without karyokinesis and cytokinesis. This leads to cells that contain a single polylobulated typical nucleus with a 2 x N ploidy. Thereafter, terminal cytoplasmic maturation occurs, leading to proplatelet formation and platelet production.The main consequence of megakaryocyte polyploidization is to augment cell size and, thus, to increase platelet production that originates from its cytoplasmic fragmentation. [2][3][4] Some researchers have also hypothesized that the level of megakaryocyte ploidy may modify platelet size and functions by altering gene regulation (reviewed by Zimmet and Ravid 5 ).Two teams have shown that endomitosis in mouse and human megakaryocytes correspond to an abortive mitotic process. 6,7 Megakaryocytes undergo a normal cycle progression with G1, S, and G2 phases. It could be demonstrated by immunofluorescence that the first stages of mitosis als...

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Human AIM-1: cDNA cloning and reduced expression during endomitosis in megakaryocyte-lineage cells

Cited by 21 publications

References 31 publications

Megakaryocytes express functional Aurora-B kinase in endomitosis

Megakaryocytes express functional Aurora-B kinase in endomitosis

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

Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes

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