Tumor suppressor roles of CENP-E and Nsl1 in<i>Drosophila</i>epithelial tissues

Clemente‐Ruiz, Marta; Muzzopappa, Mariana; Milán, Marco

doi:10.4161/cc.28417

Cited by 20 publications

(14 citation statements)

References 26 publications

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“…CENPE with two exonic indels (exons 58 and 68) and seven intronic indels was a component of the kinetochore complex and part of the spindle assembly checkpoint those were responsible for maintain chromosome congression and mitotic checkpoint [43]. It was a candidate gene for triple-negative breast cancer, and played a crucial role in suppressing tumorigenesis [44] Depletion of CENPE resulted in promoting the Drosophila epithelial tissues overgrowth [45]. …”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Resequencing of Holstein Bulls for Indel Discovery and Identification of Genes Associated with Milk Composition Traits in Dairy Cattle

et al. 2016

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The use of whole-genome resequencing to obtain more information on genetic variation could produce a range of benefits for the dairy cattle industry, especially with regard to increasing milk production and improving milk composition. In this study, we sequenced the genomes of eight Holstein bulls from four half- or full-sib families, with high and low estimated breeding values (EBVs) of milk protein percentage and fat percentage at an average effective depth of 10×, using Illumina sequencing. Over 0.9 million nonredundant short insertions and deletions (indels) [1–49 base pairs (bp)] were obtained. Among them, 3,625 indels that were polymorphic between the high and low groups of bulls were revealed and subjected to further analysis. The vast majority (76.67%) of these indels were novel. Follow-up validation assays confirmed that most (70%) of the randomly selected indels represented true variations. The indels that were polymorphic between the two groups were annotated based on the cattle genome sequence assembly (UMD3.1.69); as a result, nearly 1,137 of them were found to be located within 767 annotated genes, only 5 (0.138%) of which were located in exons. Then, by integrated analysis of the 767 genes with known quantitative trait loci (QTL); significant single-nucleotide polymorphisms (SNPs) previously identified by genome-wide association studies (GWASs) to be associated with bovine milk protein and fat traits; and the well-known pathways involved in protein, fat synthesis, and metabolism, we identified a total of 11 promising candidate genes potentially affecting milk composition traits. These were FCGR2B, CENPE, RETSAT, ACSBG2, NFKB2, TBC1D1, NLK, MAP3K1, SLC30A2, ANGPT1 and UGDH. Our findings provide a basis for further study and reveal key genes for milk composition traits in dairy cattle.

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Section: Discussionmentioning

confidence: 99%

Whole-Genome Resequencing of Holstein Bulls for Indel Discovery and Identification of Genes Associated with Milk Composition Traits in Dairy Cattle

et al. 2016

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“…In one study, CENP-E depletion alone was not sufficient to drive tumorigenesis [420]. However, another study found that knockdown of CENP-E and Nsl1 (which targets Bub3 to the kinetochore, compromising the SAC) induced a tumorigenic response [421]. These results suggest that, per se, minor chromosome congression defects are insufficient to drive tumor formation in flies and that a significant level of aneuploidy is required.…”

Section: Consequences Of Abnormal Congressionmentioning

confidence: 99%

Mechanisms of Chromosome Congression during Mitosis

Maiato

Gomes

Sousa

et al. 2017

Biology

170

176

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Chromosome congression during prometaphase culminates with the establishment of a metaphase plate, a hallmark of mitosis in metazoans. Classical views resulting from more than 100 years of research on this topic have attempted to explain chromosome congression based on the balance between opposing pulling and/or pushing forces that reach an equilibrium near the spindle equator. However, in mammalian cells, chromosome bi-orientation and force balance at kinetochores are not required for chromosome congression, whereas the mechanisms of chromosome congression are not necessarily involved in the maintenance of chromosome alignment after congression. Thus, chromosome congression and maintenance of alignment are determined by different principles. Moreover, it is now clear that not all chromosomes use the same mechanism for congressing to the spindle equator. Those chromosomes that are favorably positioned between both poles when the nuclear envelope breaks down use the so-called “direct congression” pathway in which chromosomes align after bi-orientation and the establishment of end-on kinetochore-microtubule attachments. This favors the balanced action of kinetochore pulling forces and polar ejection forces along chromosome arms that drive chromosome oscillatory movements during and after congression. The other pathway, which we call “peripheral congression”, is independent of end-on kinetochore microtubule-attachments and relies on the dominant and coordinated action of the kinetochore motors Dynein and Centromere Protein E (CENP-E) that mediate the lateral transport of peripheral chromosomes along microtubules, first towards the poles and subsequently towards the equator. How the opposite polarities of kinetochore motors are regulated in space and time to drive congression of peripheral chromosomes only now starts to be understood. This appears to be regulated by position-dependent phosphorylation of both Dynein and CENP-E and by spindle microtubule diversity by means of tubulin post-translational modifications. This so-called “tubulin code” might work as a navigation system that selectively guides kinetochore motors with opposite polarities along specific spindle microtubule populations, ultimately leading to the congression of peripheral chromosomes. We propose an integrated model of chromosome congression in mammalian cells that depends essentially on the following parameters: (1) chromosome position relative to the spindle poles after nuclear envelope breakdown; (2) establishment of stable end-on kinetochore-microtubule attachments and bi-orientation; (3) coordination between kinetochore- and arm-associated motors; and (4) spatial signatures associated with post-translational modifications of specific spindle microtubule populations. The physiological consequences of abnormal chromosome congression, as well as the therapeutic potential of inhibiting chromosome congression are also discussed.

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“…In order to confirm that intestinal dysplasia is caused by aneuploidy and not SAC impairment per se, we induced aneuploidy in ISCs either by impairing kinetochore function (and, consequently, microtubule attachment) or by inducing centrosome amplification. Successful induction of aneuploidy in Drosophila has been previously achieved by knockdown of the centromeric-associated protein meta (Cenp-meta), a kinesin-like motor protein required for efficient end-on attachment of kinetochores to the spindle microtubules [57][58]. Cenp-E knockout mice (the mammalian homolog of Cenpmeta) have also been shown to accumulate aneuploid cells [59].…”

Section: Aneuploidy Caused By Centrosome or Kinetochore Impairment Rementioning

confidence: 99%

Aneuploidy promotes intestinal dysplasia in Drosophila

Resende

Monteiro

Brás

et al. 2018

Preprint

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Aneuploidy is associated with different human diseases, particularly cancer, but how different cell types within tissues respond to aneuploidy is not fully understood. In some studies, aneuploidy has been shown to have a deleterious effect and lead to cell death, however it has also been shown to be a causal event of tumorigenesis in other contexts.Here, we show that Drosophila intestinal stem cells have a particular tolerance to aneuploidy and do not activate apoptosis in response to chromosome misegregation like other non-stem cells. Instead, we observe the development of tissue dysplasia characterized by an accumulation of progenitor cells, increased stem cell proliferation rate, and an excess of cells of the enteroendocrine lineage. Our findings highlight the importance of mechanisms acting to prevent aneuploidy within tissue stem cells and provide an in vivo model of how these cells can act as reservoirs for genomic alterations that can lead to dysplasia.

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Tumor suppressor roles of CENP-E and Nsl1 inDrosophilaepithelial tissues

Cited by 20 publications

References 26 publications

Whole-Genome Resequencing of Holstein Bulls for Indel Discovery and Identification of Genes Associated with Milk Composition Traits in Dairy Cattle

Whole-Genome Resequencing of Holstein Bulls for Indel Discovery and Identification of Genes Associated with Milk Composition Traits in Dairy Cattle

Mechanisms of Chromosome Congression during Mitosis

Aneuploidy promotes intestinal dysplasia in Drosophila

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