scholarly journals Golgi Partitioning Controls Mitotic Entry through Aurora-A Kinase

2010 ◽  
Vol 21 (21) ◽  
pp. 3708-3721 ◽  
Author(s):  
Angela Persico ◽  
Romina Ines Cervigni ◽  
Maria Luisa Barretta ◽  
Daniela Corda ◽  
Antonino Colanzi
Keyword(s):  
Cell Cycle ◽  
Golgi Complex ◽  
Cell Cycle Progression ◽  
Mitotic Checkpoint ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Mitotic Kinase ◽  
G2 Block ◽  
Golgi Fragmentation ◽  
Cell Cycle Block

At the onset of mitosis, the Golgi complex undergoes a multistep fragmentation process that is required for its correct partitioning into the daughter cells. Inhibition of this Golgi fragmentation results in cell cycle arrest at the G2 stage, suggesting that correct inheritance of the Golgi complex is monitored by a “Golgi mitotic checkpoint.” However, the molecular basis of this G2 block is not known. Here, we show that the G2-specific Golgi fragmentation stage is concomitant with centrosome recruitment and activation of the mitotic kinase Aurora-A, an essential regulator for entry into mitosis. We show that a block of Golgi partitioning impairs centrosome recruitment and activation of Aurora-A, which results in the G2 block of cell cycle progression. Overexpression of Aurora-A overrides this cell cycle block, indicating that Aurora-A is a major effector of the Golgi checkpoint. Our findings provide the basis for further understanding of the signaling pathways that coordinate organelle inheritance and cell duplication.

scholarly journals Aurora-A Abrogation of p53 DNA Binding and Transactivation Activity by Phosphorylation of Serine 215

2004 ◽  
Vol 279 (50) ◽  
pp. 52175-52182 ◽  
Author(s):  
Qiyuan Liu ◽  
Satoshi Kaneko ◽  
Lin Yang ◽  
Richard I. Feldman ◽  
Santo V. Nicosia ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Cell Cycle Progression ◽  
Target Genes ◽  
Phosphorylation Site ◽  
Dependent Manner ◽  
Aurora A ◽  
Γ Irradiation ◽  
Mitotic Kinase ◽  
Transactivation Activity

The tumor suppressor p53 is important in the decision to either arrest cell cycle progression or induce apoptosis in response to a variety of stimuli. p53 posttranslational modifications and association with other proteins have been implicated in the regulation of its stability and transactivation activity. Here we show that p53 is phosphorylated by the mitotic kinase Aurora-A at serine 215. Unlike most identified phosphorylation sites of p53 that positively associate with p53 function (Brooks, C. L., and Gu, W. (2003)Curr. Opin. Cell Biol.15, 164–171), the phosphorylation of p53 by Aurora-A at Ser-215 abrogates p53 DNA binding and transactivation activity. Downstream target genes of p53, such asp21Cip/WAF1andPTEN, were inhibited by Aurora-A in a Ser-215 phosphorylation-dependent manner (i.e.phosphomimic p53-S215D lost and non-phosphorylatable p53-S215A retained normal p53 function). As a result, Aurora-A overrides the apoptosis and cell cycle arrest induced by cisplatin and γ-irradiation, respectively. However, the effect of Aurora-A on p53 DNA binding and transactivation activity was not affected by phosphorylation of Ser-315, a recently identified Aurora-A phosphorylation site of p53 (Katayama, H., Sasai, K., Kawai, H., Yuan, Z. M., Bondaruk, J., Suzuki, F., Fujii, S., Arlinghaus, R. B., Czerniak, B. A., and Sen, S. (2004)Nat. Genet.36, 55–62). Our data indicate that phosphorylation of p53 at Ser-215 by Aurora-A is a major mechanism to inactivate p53 and can provide a molecular insight for Aurora-A function.

Aurora a kinase (AURKA) is required for male germline maintenance and regulates sperm motility in the mouse

2021 ◽  
Author(s):  
William C Lester ◽  
Taylor Johnson ◽  
Ben Hale ◽  
Nicholas Serra ◽  
Brian Elgart ◽  
...  
Keyword(s):  
Cell Division ◽  
Sperm Count ◽  
Mitotic Cell ◽  
Vital Role ◽  
Conditional Knockout ◽  
Testis Size ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Mitotic Kinase ◽  
Knockout Animals

Abstract Aurora A kinase (AURKA) is an important regulator of cell division and is required for assembly of the mitotic spindle. We recently reported the unusual finding that this mitotic kinase is also found on the sperm flagellum. To determine its requirement in spermatogenesis, we generated conditional knockout animals with deletion of the Aurka gene in either spermatogonia or spermatocytes to assess its role in mitotic and postmitotic cells, respectively. Deletion of Aurka in spermatogonia resulted in disappearance of all developing germ cells in the testis, as expected given its vital role in mitotic cell division. Deletion of Aurka in spermatocytes reduced testis size, sperm count, and fertility, indicating disruption of meiosis or an effect on spermiogenesis in developing mice. Interestingly, deletion of Aurka in spermatocytes increased apoptosis in spermatocytes along with an increase in the percentage of sperm with abnormal morphology. Despite the increase in abnormal sperm, sperm from spermatocyte Aurka knockout mice displayed increased progressive motility. In addition, sperm lysate prepared from Aurka knockout animals had decreased protein phosphatase 1 (PP1) activity. Together, our results show that AURKA plays multiple roles in spermatogenesis, from mitotic divisions of spermatogonia to sperm morphology and motility.

Three proteins required for early steps in the protein secretory pathway also affect nuclear envelope structure and cell cycle progression in fission yeast

2002 ◽  
Vol 115 (2) ◽  
pp. 421-431
Author(s):  
Anna Matynia ◽  
Sandra S. Salus ◽  
Shelley Sazer
Keyword(s):  
Cell Cycle ◽  
Nuclear Envelope ◽  
Fission Yeast ◽  
Cell Cycle Progression ◽  
Secretory Pathway ◽  
Yeast Cells ◽  
Ran Gtpase ◽  
A Cell ◽  
Cell Cycle Block ◽  
Er Membrane

The Ran GTPase is an essential protein that has multiple functions in eukaryotic cells. Fission yeast cells in which Ran is misregulated arrest after mitosis with condensed, unreplicated chromosomes and abnormal nuclear envelopes. The fission yeast sns mutants arrest with a similar cell cycle block and interact genetically with the Ran system. sns-A10, sns-B2 and sns-B9 have mutations in the fission yeast homologues of S. cerevisiae Sar1p, Sec31p and Sec53p, respectively, which are required for the early steps of the protein secretory pathway. The three sns mutants accumulate a normally secreted protein in the endoplasmic reticulum (ER), have an increased amount of ER membrane, and the ER/nuclear envelope lumen is dilated. Neither a post-ER block in the secretory pathway, nor ER proliferation caused by overexpression of an integral ER membrane protein, results in a cell cycle-specific defect. Therefore, the arrest seen in sns-A10, sns-B2 and sns-B9 is most likely due to nuclear envelope defects that render the cells unable to re-establish the interphase organization of the nucleus after mitosis. As a consequence, these mutants are unable to decondense their chromosomes or to initiate of the next round of DNA replication.

scholarly journals A Mitotic GlcNAcylation/Phosphorylation Signaling Complex Alters the Posttranslational State of the Cytoskeletal Protein Vimentin

2008 ◽  
Vol 19 (10) ◽  
pp. 4130-4140 ◽  
Author(s):  
Chad Slawson ◽  
T. Lakshmanan ◽  
Spencer Knapp ◽  
Gerald W. Hart
Keyword(s):  
Cell Cycle ◽  
Protein Modification ◽  
Cell Cycle Progression ◽  
Stress Hormones ◽  
Aurora B ◽  
Intermediate Filament Protein ◽  
Mitotic Kinase ◽  
Transient Complex ◽  
M Phase ◽  
Mitotic Phosphorylation

O-linked β-N-acetylglucosamine (O-GlcNAc) is a highly dynamic intracellular protein modification responsive to stress, hormones, nutrients, and cell cycle stage. Alterations in O-GlcNAc addition or removal (cycling) impair cell cycle progression and cytokinesis, but the mechanisms are not well understood. Here, we demonstrate that the enzymes responsible for O-GlcNAc cycling, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are in a transient complex at M phase with the mitotic kinase Aurora B and protein phosphatase 1. OGT colocalized to the midbody during telophase with Aurora B. Furthermore, these proteins coprecipitated with each other in a late mitotic extract. The complex was stable under Aurora inhibition; however, the total cellular levels of O-GlcNAc were increased and the localization of OGT was decreased at the midbody after Aurora inhibition. Vimentin, an intermediate filament protein, is an M phase substrate for both Aurora B and OGT. Overexpression of OGT or OGA led to defects in mitotic phosphorylation on multiple sites, whereas OGT overexpression increased mitotic GlcNAcylation of vimentin. OGA inhibition caused a decrease in vimentin late mitotic phosphorylation but increased GlcNAcylation. Together, these data demonstrate that the O-GlcNAc cycling enzymes associate with kinases and phosphatases at M phase to regulate the posttranslational status of vimentin.

scholarly journals Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 6003
Author(s):  
Majd S. Hijjawi ◽  
Reem Fawaz Abutayeh ◽  
Mutasem O. Taha
Keyword(s):  
Anticancer Agents ◽  
Cell Cycle Progression ◽  
Kinase Inhibitors ◽  
Epithelial Mesenchymal Transition ◽  
Resonance Energy ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Characteristic Analysis ◽  
Mesenchymal Transition ◽  
Intermolecular Contacts

Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.

Regulation and Targeting of Eg5 in Blast Crisis CML: Overcoming Imatinib Resistance.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2877-2877
Author(s):  
Bing Z. Carter ◽  
Duncan Mak ◽  
Yue-Xi Shi ◽  
Wendy D. Schober ◽  
Rui-Yu Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Cell Cycle Progression ◽  
Blast Crisis ◽  
Cycle Progression ◽  
Tyrosine Kinase Signaling ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant ◽  
Cell Cycle Block

Abstract Imatinib (STI571), a tyrosine kinase inhibitor, is becoming the new standard of care for patients with chronic and advanced phase CML. However, the treatment for blast crisis (BC) CML is less effective. Resistance to Imatinib develops in all phases, particularly in BC CML emphasizing the need for alternative therapies. Eg5, a microtubule-associated motor protein plays an important role in establishing a bipolar spindle during mitosis and is essential for cell cycle progression. Eg5 was recently found to be highly expressed in BC CML by microarray analysis (Oncogene22:3952–3963, 2003). In this study, we examined the regulation of Eg5 by Bcr-Abl tyrosine kinase signaling and tested Eg5 as a potential therapeutic target in BC CML and Imatinib resistant CML. We found that Eg5 is expressed in all Philadelphia chromosome positive (Ph+) CML cell lines and in BC CML patient samples. Inhibition of Bcr-Abl activity by Imatinib downregulated Eg5 expression in Imatinib sensitive KBM5 cells (a cell line derived from the blasts of a BC CML patient) and HL-60p185 cells (HL-60 cells transfected with Bcr-Abl fusion protein p185), but not in Imatinib resistant KBM5-STI571 cells and Bcr-Abl negative HL-60 cells suggesting that Eg5 is a downstream effector of Bcr-Abl and is regulated by Bcr-Abl tyrosine kinase signaling in Ph+ cells. Blocking Eg5 expression by its antisense oligonucleotide (Eg5-AS) induced G2/M cell cycle block, and subsequent cell death in both Imatinib sensitive KBM5 cells and Imatinib resistant KBM5-STI571 cells. At 48 hrs, 15.8±5.5% of KBM5 cells and 22.7±10.7% of KBM5-STI571 cells were blocked in G2/M in Eg5-AS treated cells compared to 3.5±1.9% and 7.6±1.4%, respectively, of the mismatched oligonucleotide (Eg5-NS) treated cells. Induction of cell death was observed at 72 hrs (29.1±1.9% in KBM5 and 29.4±1.1 % in KBM5-STI571 cells in Eg5-AS treated compared to 12.5±0.28% and 13.7±1.6% of Eg5-NS treated cells). Metaphase arrest due to disruption of bipolar spindle formation, loss of mitochondrial membrane potential, and caspase activation were observed in both cell lines. Similarly, inhibition of Eg5 activity by a small molecular inhibitor, S-trityl-L-cysteine, induced cell cycle block and cell death indistinguishably in Imatinib sensitive KBM5 and Ba/F3Bcr-Ablwt cells and in Imatinib resistant KBM5-STI571, Ba/F3Bcr-AblE255K, and Ba/F3Bcr-AblT315I cells. Treatment of Scid mice starting 7 days after injection of KBM5 cells with Eg5-AS, 25 mg/kg, 3 times a week for 3 weeks, significantly prolonged the survival of the animals (64 days vs. 49 days of Eg5-NS treated mice, p=0.0344). The effect of Eg5 inhibition on survival of Scid mice harboring Imatinib resistant KBM5-STI571 cells is currently under investigation. Our studies suggest that Eg5 is a downstream target of Bcr-Abl tyrosine kinase. Inhibition of Eg5 expression or its activity blocks cell cycle progression and induces cell death regardless of cell response to Imatinib. Eg5 could be a potential new critical therapeutic target for the treatment of Imatinib resistant CML and BC CML.

Analysis of Aurora Kinase Expressions and Cell Cycle Regulation by Aurora-C in Leukemia Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1366-1366 ◽  
Author(s):  
Miki Kobayashi ◽  
Satoki Nakamura ◽  
Takaaki Ono ◽  
Yuya Sugimoto ◽  
Naohi Sahara ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Western Blot ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Human Leukemia ◽  
Aurora A ◽  
Aurora Kinases

Abstract Background: The conserved Aurora family kinases, a family of mitotic serine/threonine kinases, have three members (Aurora-A, -B and -C) in mammalian cells. The Aurora kinases are involved in the regulation of cell cycle progression, and alterations in their expression have been shown to associate with cell malignant transformation. Aurora A localizes to the centrosomes during anaphase, and it is required for mitotic entry. Aurora B regulates the formation of a stable bipolar spindle-kinetochore attachment in mitosis. The function of Aurora-C in mammalian cells has not been studied extensively. In this study, we investigated that human leukemia cells expressed all 3 Aurora kinases at both protein and mRNA level, and the mechanisms of cell cycle regulation by knock down of Aurora C in leukemia cells. Methods: In this study, we used the 7 human leukemia cell lines, K562, NB4, HL60, U937, CEM, MOLT4, SUP-B15 cells. The expression levels of mRNA and proteins of Aurora kinases were evaluated by RT-PCR and western blot. The analysis of proliferation and cell cycle were performed by MTT assay and FCM, respectively. Results: The mRNA of Aurora-A and Aurora-B are highly expressed in human leukemia cell lines (K562, NB4, HL60, U937, CEM, MOLT4, SUP-B15 cells), while the mRNA of Aurora C is not only expressed highly in all cells. In contrast, an increase in the protein level of the 3 kinases was found in all cell lines. These observations suggested posttranscriptional mechanisms, which modulate the expression of Aurora C. In cell cycle analysis by flow cytometory, the knock down of Aurora C by siRNA induced G0/G1 arrest and apoptosis in leukemia cells, and increased the protein levels of p27Kip1 and decreased Skp2 by western blot. In MTT assay, it was revealed that the growth inhibition of leukemia cells transfected with siRNA Aurora C compared with leukemia cells untransfected with siRNA Aurora C. Moreover, We showed that Aurora C was associated with Survivin and directly bound to Survivin by immunoprecipitation and western blot. Conclusion: We found that human leukemia cells expressed all 3 members of the Aurora kinase family. These results suggest that the Aurora kinases may play a relevant role in leukemia cells. Among these Aurora kinases, Aurora C interacted with Survivin and prevented apoptosis of leukemia cells, and induced cell cycle progression. Our results showed that Aurora-C may serve as a key regulator in cell division and survival. These results suggest that the Aurora C kinase may play an important role in leukemia cells, and may represent a target for leukemia therapy.

Combined Inhibition of Janus and Aurora Kinases by the Novel Small Molecule Inhibitor AZD1480 Induces Cell Death and Downregulates PD-L1 and PD-L2 Expression In Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2848-2848
Author(s):  
Enrico Derenzini ◽  
Daniela Buglio ◽  
Hiroshi Katayama ◽  
Yuan Ji ◽  
Subrata Sen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Death ◽  
Cell Lines ◽  
Immune Escape ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Aurora Kinases ◽  
Mitotic Block ◽  
Dose Dependent

Abstract Abstract 2848 Hodgkin Lymphoma (HL) cell proliferation and survival is sustained by a complex network of cytokine signaling, involving the Hodgkin and Reed-Sternberg cells and tumor microenvironment. Following cytokine stimulation, JAK-STAT activation promotes the transcription of target genes involved in proliferation, survival, and immune escape. Programmed Death-ligands 1 and 2 (PD-L1 and PD-L2) and the Th2 chemokine TARC are immune-modulators involved in immune evasion, respectively through inhibition of effector T cell function (PD-L1, PD-L2) and attraction and homing of Th2 cells (TARC). Aurora kinases are frequently overexpressed in human cancers and play essential functions in chromosome alignment and cytokinesis. The role of Aurora kinases in Hodgkin lymphomagenesis is not defined yet. In this study we report the activity profile of the JAK2 inhibitor AZD1480 in HL cell lines (HD-LM2, L-428, KM-H2, L-540). To assess the effect of AZD1480 on cell proliferation, cells were incubated with increasing concentrations of AZD1480 (from 0.1 to 10 μM) for 24, 48 and 72 hours (hrs). A significant growth inhibition was evident after 72 hrs of incubation, specially using the high doses of AZD1480 (5μM). The L-540 cell line showed the highest sensitivity, with a decrease in cell viability close to 50% following incubation with AZD1480 1μM. Inhibition of STAT3, STAT5 and STAT6 phosphorylation in the L-540, L-428 and HD-LM2 cell lines was observed with concentrations equal to 0.1 μM or higher. Using Annexin V- propidium iodide staining, we found that AZD1480 induced cell death by apoptosis in a dose dependent manner after 72 hrs of incubation when a high concentration (5μM) of the drug was used. Lower concentrations of AZD1480 (1μM) promoted a statistically significant increase in cell death only in the L-540 and to a lesser extent in the L-428 cell line. Consistent with this data, also caspase 9, 3 and PARP cleavage was observed in all the cell lines exposed to AZD1480 5 μM. AZD1480 5μM promoted a marked increase in the G2/M fraction in all the cell lines as soon as 24 hrs after incubation, especially in the HD-LM2 and L-428 cell lines. Treatment with lower doses (1μM) did not affect significantly the cell cycle. Since AZD1480 was also reported to inhibit Aurora A kinase at nanomolar concentrations in enzymatic assays, we assessed if the significant increase in the G2/M fraction was related to the inhibition of the Aurora A kinase. We evaluated the levels of autophosphorylation on Thr-288 by western blotting. Cells were pretreated with Nocodazole 400 ng/ml for 18 hrs in order to achieve a mitotic block, and then exposed to AZD1480 (1-5μM) and/or the proteasome inhibitor MG132 (20μM) (in order to prevent the potential overriding of the Nocodazole induced mitotic block), for 3 hours. A dose-dependent inhibition of Aurora A was detected in all the cell lines, with a complete abrogation when higher doses of AZD1480 were used (5μM). These findings are consistent with the analysis of the cell cycle fractions, showing dose-dependent changes of the cell cycle at 24 hrs following incubation with AZD1480. AZD1480 also decreased the secretion of key cytokines involved autocrine and paracrine survival loops and immune escape. Following incubation with AZD1480 1μM for 72 hrs cell culture supernatants were analyzed by ELISA: decreased levels of IL-6, IL-13, TARC, and IL-21 were observed in HD-LM2, L-428 and L-540 cells. Moreover we assessed the expression of PD-L1 and PD-L2 by flow cytometry and observed significant downregulation in the PD-L1/PD-L2 overexpressing cell lines (L-540 and HD-LM2). These data suggest that AZD1480 has a pleiotropic mechanism of action in HL by targeting the JAK-STAT and the Aurora kinase pathway, and by altering the pattern of cytokine and chemokine secretion and the expression of factors involved in immune escape. Our study provides the rationale for further clinical investigation of AZD1480 in HL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Budding Yeast Bub2 Is Localized at Spindle Pole Bodies and Activates the Mitotic Checkpoint via a Different Pathway from Mad2

1999 ◽  
Vol 145 (5) ◽  
pp. 979-991 ◽  
Author(s):  
Roberta Fraschini ◽  
Elisa Formenti ◽  
Giovanna Lucchini ◽  
Simonetta Piatti
Keyword(s):  
Cell Cycle ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Spindle Pole Body ◽  
Mitotic Checkpoint ◽  
Spindle Pole ◽  
Cycle Progression ◽  
Spindle Pole Bodies

The mitotic checkpoint blocks cell cycle progression before anaphase in case of mistakes in the alignment of chromosomes on the mitotic spindle. In budding yeast, the Mad1, 2, 3, and Bub1, 2, 3 proteins mediate this arrest. Vertebrate homologues of Mad1, 2, 3, and Bub1, 3 bind to unattached kinetochores and prevent progression through mitosis by inhibiting Cdc20/APC-mediated proteolysis of anaphase inhibitors, like Pds1 and B-type cyclins. We investigated the role of Bub2 in budding yeast mitotic checkpoint. The following observations indicate that Bub2 and Mad1, 2 probably activate the checkpoint via different pathways: (a) unlike the other Mad and Bub proteins, Bub2 localizes at the spindle pole body (SPB) throughout the cell cycle; (b) the effect of concomitant lack of Mad1 or Mad2 and Bub2 is additive, since nocodazole-treated mad1 bub2 and mad2 bub2 double mutants rereplicate DNA more rapidly and efficiently than either single mutant; (c) cell cycle progression of bub2 cells in the presence of nocodazole requires the Cdc26 APC subunit, which, conversely, is not required for mad2 cells in the same conditions. Altogether, our data suggest that activation of the mitotic checkpoint blocks progression through mitosis by independent and partially redundant mechanisms.

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