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      Modeling potent pathways for APC/C inhibition: pivotal roles for MCC and BubR1

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          Abstract

          The highly conserved spindle assembly checkpoint (SAC) ensures that the sister chromatids of the duplicated genome are not separated and distributed to the spindle poles before all chromosomes have been properly linked to the microtubules of the mitotic spindle. Biochemically, the SAC delays cell cycle progression by preventing activation of the anaphase-promoting complex (APC/C) or cyclosome; whose activation by Cdc20 is required for sister-chromatid separation, which marks the transition into anaphase. In response to activation of the checkpoint, various species control the activity of both APC/C and Cdc20. However, the underlying regulatory pathways remain largely elusive. In this study, five possible model variants of APC/C regulation were constructed, namely BubR1, Mad2, MCC, MCF2 and an all-pathways model variant. These models are validated with experimental data from the literature. A wide range of parameter values have been tested to find critical values of the APC binding rate. The results show that all variants are able to capture the wild type behaviour of the APC. However, only one model variant, which included both MCC as well as BubR1 as potent inhibitors of the APC, was able to reproduce both wild type and mutant type behaviour of APC regulation. The presented work has successfully distinguished between five competing dynamical models of the same biological system using a systems biology approach. Furthermore, the results suggest that systems-level approach is vital for molecular biology and could also be used for compare the pathways of relevance with the objective to generate hypotheses and improve our understanding.

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          Most cited references43

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          Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis.

          The mitotic checkpoint is a major cell cycle control mechanism that guards against chromosome missegregation and the subsequent production of aneuploid daughter cells. Most cancer cells are aneuploid and frequently missegregate chromosomes during mitosis. Indeed, aneuploidy is a common characteristic of tumours, and, for over 100 years, it has been proposed to drive tumour progression. However, recent evidence has revealed that although aneuploidy can increase the potential for cellular transformation, it also acts to antagonize tumorigenesis in certain genetic contexts. A clearer understanding of the tumour suppressive function of aneuploidy might reveal new avenues for anticancer therapy.
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            Feedback control of mitosis in budding yeast.

            R Li, A Murray (1991)
            We have investigated the feedback control that prevents cells with incompletely assembled spindles from leaving mitosis. We isolated budding yeast mutants sensitive to the anti-microtubule drug benomyl. Mitotic arrest-deficient (mad) mutants are the subclass of benomyl-sensitive mutants in which the completion of mitosis is not delayed in the presence of benomyl and that die as a consequence of their premature exit from mitosis. A number of properties of the mad mutants indicate that they are defective in the feedback control over the exit from mitosis: their killing by benomyl requires passage through mitosis; their benomyl sensitivity can be suppressed by an independent method for delaying the exit from mitosis; they have normal microtubules; and they have increased frequencies of chromosome loss. We cloned MAD2, which encodes a putative calcium-binding protein whose disruption is lethal. We discuss the role of feedback controls in coordinating events in the cell cycle.
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              S. cerevisiae genes required for cell cycle arrest in response to loss of microtubule function.

              We have identified mutant strains of S. cerevisiae that fail to properly arrest their cell cycles at mitosis in response to the loss of microtubule function. New bud emergence and DNA replication (but not cytokinesis) occur with high efficiency in the mutants under conditions that inhibit these events in wild-type cells. The inability to halt cell cycle progression is specific for impaired microtubule function; the mutants respond normally to other cell cycle-blocking treatments. Under microtubule-disrupting conditions, the mutants neither achieve nor maintain the high level of histone H1 kinase activity characteristic of wild-type cells. Our studies have defined three genes required for normal cell cycle arrest. These findings are consistent with the existence of a surveillance system that halts the cell cycle in response to microtubule perturbation.
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                Author and article information

                Journal
                2016-11-15
                Article
                10.1089/omi.2015.0027
                1611.04781
                eb710045-dc21-4c60-860a-3e46eb01f831

                http://arxiv.org/licenses/nonexclusive-distrib/1.0/

                History
                Custom metadata
                OMICS: A Journal of Integrative Biology. May 2015, 19(5): 294-305
                Journal article as preprint
                q-bio.MN q-bio.CB

                Cell biology,Molecular biology
                Cell biology, Molecular biology

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