Role of the kinetochore/cell cycle checkpoint protein ZW10 in interphase cytoplasmic dynein function

Zeste white 10 (ZW10) is a mitotic checkpoint protein and the anchor for cytoplasmic dynein at mitotic kinetochores, though it is expressed throughout the cell cycle. We find that ZW10 localizes to pericentriolar membranous structures during interphase and cosediments with Golgi membranes. Dominant-negative ZW10, anti-ZW10 antibody, and ZW10 RNA interference (RNAi) caused Golgi dispersal. ZW10 RNAi also dispersed endosomes and lysosomes. Live imaging of Golgi, endosomal, and lysosomal markers after reduced ZW10 expression showed a specific decrease in the frequency of minus end–directed movements. Golgi membrane–associated dynein was markedly decreased, suggesting a role for ZW10 in dynein cargo binding during interphase. We also find ZW10 enriched at the leading edge of migrating fibroblasts, suggesting that ZW10 serves as a general regulator of dynein function throughout the cell cycle.

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Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis

The Journal of Cell Biology ◽

10.1083/jcb.200706015 ◽

2007 ◽

Vol 179 (2) ◽

pp. 255-267 ◽

Cited By ~ 147

Author(s):

Karthik Jeganathan ◽

Liviu Malureanu ◽

Darren J. Baker ◽

Susan C. Abraham ◽

Jan M. van Deursen

Keyword(s):

Cell Death ◽

Chromosome Segregation ◽

Physiological Role ◽

Mitotic Checkpoint ◽

Critical Threshold ◽

Wild Type ◽

Checkpoint Protein ◽

Chromosome Missegregation ◽

Mitotic Checkpoint Protein

The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate.

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The J Domain of Tpr2 Regulates Its Interaction with the Proapoptotic and Cell-Cycle Checkpoint Protein, Rad9

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2001.5685 ◽

2001 ◽

Vol 287 (4) ◽

pp. 932-940 ◽

Cited By ~ 8

Author(s):

Shuang-Lin Xiang ◽

Tomoyasu Kumano ◽

Shu-ichi Iwasaki ◽

Xiangao Sun ◽

Kastuji Yoshioka ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Checkpoint ◽

Checkpoint Protein ◽

Cycle Checkpoint ◽

J Domain

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Abnormal Micronuclear Telomeres Lead to an Unusual Cell Cycle Checkpoint and Defects in Tetrahymena Oral Morphogenesis

Eukaryotic Cell ◽

10.1128/ec.00393-07 ◽

2008 ◽

Vol 7 (10) ◽

pp. 1712-1723 ◽

Cited By ~ 3

Author(s):

Karen E. Kirk ◽

Christina Christ ◽

Jennifer M. McGuire ◽

Arun G. Paul ◽

Mithaq Vahedi ◽

...

Keyword(s):

Cell Cycle ◽

Mitotic Spindle ◽

Tetrahymena Thermophila ◽

Germ Line ◽

Cell Cycle Checkpoint ◽

Dna Damage Checkpoint ◽

Telomeric Dna ◽

Spindle Apparatus ◽

Cycle Checkpoint

ABSTRACT Telomere mutants have been well studied with respect to telomerase and the role of telomere binding proteins, but they have not been used to explore how a downstream morphogenic event is related to the mutated telomeric DNA. We report that alterations at the telomeres can have profound consequences on organellar morphogenesis. Specifically, a telomerase RNA mutation termed ter1-43AA results in the loss of germ line micronuclear telomeres in the binucleate protozoan Tetrahymena thermophila. These cells also display a micronuclear mitotic arrest, characterized by an extreme delay in anaphase with an elongated, condensed chromatin and a mitotic spindle apparatus. This anaphase defect suggests telomere fusions and consequently a spindle rather than a DNA damage checkpoint. Most surprisingly, these mutants exhibit unique, dramatic defects in the formation of the cell's oral apparatus. We suggest that micronuclear telomere loss leads to a “dynamic pause” in the program of cortical development, which may reveal an unusual cell cycle checkpoint.

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Search, capture and signal: games microtubules and centrosomes play

Journal of Cell Science ◽

10.1242/jcs.114.2.247 ◽

2001 ◽

Vol 114 (2) ◽

pp. 247-255 ◽

Cited By ~ 5

Author(s):

S.C. Schuyler ◽

D. Pellman

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Cytoplasmic Dynein ◽

Cell Cycle Checkpoint ◽

Cellular Polarity ◽

Cycle Progression ◽

Cycle Checkpoint ◽

Dividing Cells ◽

Actin Cables ◽

Type V

Accurate distribution of the chromosomes in dividing cells requires coupling of cellular polarity cues with both the orientation of the mitotic spindle and cell cycle progression. Work in budding yeast has demonstrated that cytoplasmic dynein and the kinesin Kip3p define redundant pathways that ensure proper spindle orientation. Furthermore, it has been shown that the Kip3p pathway components Kar9p and Bim1p (Yeb1p) form a complex that provides a molecular link between cortical polarity cues and spindle microtubules. Recently, other studies indicated that the cortical localization of Kar9p depends upon actin cables and Myo2p, a type V myosin. In addition, a BUB2-dependent cell cycle checkpoint has been described that inhibits the mitotic exit network and cytokinesis until proper centrosome position is achieved. Combined, these studies provide molecular insight into how cells link cellular polarity, spindle position and cell cycle progression.

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Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following γ-irradiation

Biochimie ◽

10.1016/0300-9084(96)88161-2 ◽

1995 ◽

Vol 77 (6) ◽

pp. 462-465 ◽

Cited By ~ 39

Author(s):

M. Masutani ◽

T. Nozaki ◽

K. Wakabayashi ◽

T. Sugimura

Keyword(s):

Cell Cycle ◽

Cell Cycle Checkpoint ◽

Γ Irradiation ◽

Cycle Checkpoint

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The Maize Homologue of the Cell Cycle Checkpoint Protein MAD2 Reveals Kinetochore Substructure and Contrasting Mitotic and Meiotic Localization Patterns

The Journal of Cell Biology ◽

10.1083/jcb.145.3.425 ◽

1999 ◽

Vol 145 (3) ◽

pp. 425-435 ◽

Cited By ~ 73

Author(s):

Hong-Guo Yu ◽

Michael G. Muszynski ◽

R. Kelly Dawe

Keyword(s):

Cell Cycle ◽

Spindle Assembly ◽

Cell Cycle Checkpoint ◽

Checkpoint Protein ◽

Microtubule Attachment ◽

Checkpoint Pathway ◽

Outer Domain ◽

Cycle Checkpoint ◽

Mitosis And Meiosis ◽

Meiosis I

We have identified a maize homologue of yeast MAD2, an essential component in the spindle checkpoint pathway that ensures metaphase is complete before anaphase begins. Combined immunolocalization of MAD2 and a recently cloned maize CENPC homologue indicates that MAD2 localizes to an outer domain of the prometaphase kinetochore. MAD2 staining was primarily observed on mitotic kinetochores that lacked attached microtubules; i.e., at prometaphase or when the microtubules were depolymerized with oryzalin. In contrast, the loss of MAD2 staining in meiosis was not correlated with initial microtubule attachment but was correlated with a measure of tension: the distance between homologous or sister kinetochores (in meiosis I and II, respectively). Further, the tension-sensitive 3F3/2 phosphoepitope colocalized, and was lost concomitantly, with MAD2 staining at the meiotic kinetochore. The mechanism of spindle assembly (discussed here with respect to maize mitosis and meiosis) is likely to affect the relative contributions of attachment and tension. We support the idea that MAD2 is attachment-sensitive and that tension stabilizes microtubule attachments.

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Cell cycle checkpoint defects in gastrointestinal malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.680 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 680-680

Author(s):

Ramya Thota ◽

Mark Andrew Lewis ◽

Lincoln Nadauld ◽

Derrick S. Haslem ◽

Terence Duane Rhodes ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Checkpoint ◽

Targeted Agents ◽

Gastrointestinal Malignancies ◽

Cyclin Dependent Kinases ◽

Cycle Checkpoint ◽

Cell Cycle Pathway ◽

Cycle Regulation ◽

Uncontrolled Cell Proliferation

680 Background: Cyclin Dependent Kinases (CDKs) play a significant role in cell cycle regulation. Aberrations involving the cell cycle pathway genes can lead to uncontrolled cell proliferation and genomic instability. These could potentially be targeted with CDK4/6 inhibitors. The frequency and type of these alterations in GI tumors is largely unknown. Methods: We analyzed the frequency of abnormalities in cell cycle genes in patients with diverse GI malignancies (colorectal, liver, pancreas, gastroesophageal, anal, appendix) that underwent next generation sequencing from January 2013 to August 2017. Results: Aberrations in the cell cycle pathway were identified in 33 of 299 (11%) of cancers. The frequency of aberrations was as follows: CDKN2A/B in 10 (30.3%), CCND1 in 7 patients (pts) (21.2%), CCND2 in 2 pts (6%), CEBPA in 2 pts (6%), CDK6 in 2 pts (6%), CDK8 in 2 pts (6%) and CDK2 in 1 (3%). Alteration involving multiple genes of cell cycle noted in 7 patients (21.2%) with combination of CCND1 and CDKN2A being most common combination. The cell cycle checkpoint defects were most frequently seen in 9 pts with colon (27%), 8 pts with hepatobiliary (27%), 8 pts with pancreatic (24%), 7 pts with esophageal (21%), and less commonly in small bowel (6%) and GIST (6%). Conclusions: The alterations in the cell cycle pathway are most common in certain GI tumors mainly colon, pancreatic, hepatobiliary and esophageal tumors. Future clinical trials exploring the potential role of targeted agents such as CDK4/6 inhibitors alone or in combination with other targeted agents such as MEK inhibitors requires further exploration in these tumors.

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