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      Spindle checkpoint–independent inhibition of mitotic chromosome segregation by Drosophila Mps1

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          Abstract

          The conserved protein kinase Mps1 is required for the spindle assembly checkpoint (SAC). It is also involved in correction of erroneous attachments of kinetochores to the mitotic spindle before anaphase onset. Characterization of Drosophila Mps1 reveals yet another function: SAC-independent inhibition of sister chromatid separation.

          Abstract

          Monopolar spindle 1 (Mps1) is essential for the spindle assembly checkpoint (SAC), which prevents anaphase onset in the presence of misaligned chromosomes. Moreover, Mps1 kinase contributes in a SAC-independent manner to the correction of erroneous initial attachments of chromosomes to the spindle. Our characterization of the Drosophila homologue reveals yet another SAC-independent role. As in yeast, modest overexpression of Drosophila Mps1 is sufficient to delay progression through mitosis during metaphase, even though chromosome congression and metaphase alignment do not appear to be affected. This delay in metaphase depends on the SAC component Mad2. Although Mps1 overexpression in mad2 mutants no longer causes a metaphase delay, it perturbs anaphase. Sister kinetochores barely move apart toward spindle poles. However, kinetochore movements can be restored experimentally by separase-independent resolution of sister chromatid cohesion. We propose therefore that Mps1 inhibits sister chromatid separation in a SAC-independent manner. Moreover, we report unexpected results concerning the requirement of Mps1 dimerization and kinase activity for its kinetochore localization in Drosophila. These findings further expand Mps1's significance for faithful mitotic chromosome segregation and emphasize the importance of its careful regulation.

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          The spindle-assembly checkpoint in space and time.

          In eukaryotes, the spindle-assembly checkpoint (SAC) is a ubiquitous safety device that ensures the fidelity of chromosome segregation in mitosis. The SAC prevents chromosome mis-segregation and aneuploidy, and its dysfunction is implicated in tumorigenesis. Recent molecular analyses have begun to shed light on the complex interaction of the checkpoint proteins with kinetochores--structures that mediate the binding of spindle microtubules to chromosomes in mitosis. These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression.
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            The conserved KMN network constitutes the core microtubule-binding site of the kinetochore.

            The microtubule-binding interface of the kinetochore is of central importance in chromosome segregation. Although kinetochore components that stabilize, translocate on, and affect the polymerization state of microtubules have been identified, none have proven essential for kinetochore-microtubule interactions. Here, we examined the conserved KNL-1/Mis12 complex/Ndc80 complex (KMN) network, which is essential for kinetochore-microtubule interactions in vivo. We identified two distinct microtubule-binding activities within the KMN network: one associated with the Ndc80/Nuf2 subunits of the Ndc80 complex, and a second in KNL-1. Formation of the complete KMN network, which additionally requires the Mis12 complex and the Spc24/Spc25 subunits of the Ndc80 complex, synergistically enhances microtubule-binding activity. Phosphorylation by Aurora B, which corrects improper kinetochore-microtubule connections in vivo, reduces the affinity of the Ndc80 complex for microtubules in vitro. Based on these findings, we propose that the conserved KMN network constitutes the core microtubule-binding site of the kinetochore.
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              Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product.

              Six monoclonal antibodies have been isolated from mice immunized with synthetic peptide immunogens whose sequences are derived from that of the human c-myc gene product. Five of these antibodies precipitate p62c-myc from human cells, and three of these five also recognize the mouse c-myc gene product. None of the antibodies sees the chicken p110gag-myc protein. All six antibodies recognize immunoblotted p62c-myc. These reagents also provide the basis for an immunoblotting assay by which to quantitate p62c-myc in cells.
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                Author and article information

                Contributors
                Role: Monitoring Editor
                Journal
                Mol Biol Cell
                Mol. Biol. Cell
                molbiolcell
                mbc
                Mol. Bio. Cell
                Molecular Biology of the Cell
                The American Society for Cell Biology
                1059-1524
                1939-4586
                15 June 2012
                : 23
                : 12
                : 2275-2291
                Affiliations
                [1] aInstitute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
                [2] bCentre National de la Recherche Scientifique, Institut Jacques Monod, Unité Mixte de Recherche 7592, Université Paris Diderot, Paris Cedex 13, France
                Instituto Gulbenkian de Ciência
                Author notes
                *Address correspondence to: Christian F. Lehner ( christian.lehner@ 123456imls.uzh.ch ).
                Article
                E12-02-0117
                10.1091/mbc.E12-02-0117
                3374747
                22553353
                ace44ddc-c852-4c62-b23d-451c720d8e0c
                © 2012 Althoff et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( http://creativecommons.org/licenses/by-nc-sa/3.0).

                “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.

                History
                : 14 February 2012
                : 17 April 2012
                : 24 April 2012
                Categories
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                Cell Cycle
                A Highlights from MBoC Selection

                Molecular biology
                Molecular biology

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