Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation

Ganem, Neil J.; Cornils, Hauke; Chiu, Shang-Yi; O’Rourke, Kevin P.; Arnaud, Jonathan; Yimlamai, Dean; Théry, Manuel; Camargo, Fernando D.; Pellman, David

doi:10.1016/j.cell.2014.06.029

Cited by 330 publications

(415 citation statements)

References 49 publications

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“…S1) undergo recurrent cell cycle progression at least for up to 64 h in the presence of colcemid. One possible reason is weaken tetraploid checkpoint by p53 inactivation and weaken Hippo pathway as previously reported (Nitta et al, 2002;Ganem et al, 2014). On the other hand, polyploid cells with numerous micronuclei do not undergo further cell cycle progression ( Supplementary Fig.…”

Section: Dna Ploidy Increases During Micronucleation In A9 Cellsmentioning

confidence: 91%

Recurrent Micronucleation through Cell Cycle Progression in the Presence of Microtubule Inhibitors

Nakayama

Uno

et al. 2015

Cell Struct. Funct.

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ABSTRACT. Although most cell lines undergo mitotic arrest after prolonged exposure to microtubule inhibitors, some cells subsequently exit this state and become tetraploid. Among these cells, limited numbers of rodent cells are known to undergo multinucleation to generate multiple small independent nuclei, or micronuclei by prolonged colcemid treatment. Micronuclei are thought to be formed when cells shift to a pseudo G1 phase, during which the onset of chromosomal decondensation allows individual chromosomes distributed throughout the cell to serve as sites for the reassembly of nuclear membranes. To better define this process, we used longterm live cell imaging to observe micronucleation induced in mouse A9 cells by treating with the microtubule inhibitor colcemid. Our observations confirm that nuclear envelope formation occurs when mitotic-arrested cells shift to a pseudo G1 phase and adopt a tetraploid state, accompanied by chromosome decondensation. Unexpectedly, only a small number of cells containing large micronuclei were formed. We found that tetraploid micronucleated cells proceeded through an additional cell cycle, shifting to a pseudo G1 phase and forming octoploid micronucleated cells that were smaller and more numerous compared with the tetraploid micronucleated cells. Our data suggest that micronucleation occur when cells shift from mitotic arrest to a pseudo G1 phase, and demonstrate that, rather than being a single event, micronucleation is an inducible recurrent process that leads to the formation of progressively smaller and more numerous micronuclei.

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Section: Dna Ploidy Increases During Micronucleation In A9 Cellsmentioning

confidence: 91%

Recurrent Micronucleation through Cell Cycle Progression in the Presence of Microtubule Inhibitors

Nakayama

Uno

et al. 2015

Cell Struct. Funct.

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“…11,17,18 Finally, centrosome amplification was identified as the upstream signal triggering CASP2 activation upon cytokinesis abortion. 15 It remains to elucidate how and whether BCL9L and other factors responding to non-diploidy, including large tumor suppressor kinase 2 (LATS2) and the Hyppo pathway, 19 BCL2 proteins, 6 mitogen-activated protein kinase 14 (MAPK14, best known as p38), 9 Cyclin D1 (CCND1) 20 and ubiquitin specific peptidase 28 (USP28), 17,18 may contribute to this CASP2-dependent process.…”

mentioning

confidence: 99%

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

Vitale

Manic

Castedo

et al. 2017

Molecular & Cellular Oncology

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Mitotic catastrophe is an oncosuppressive mechanism that targets cells experiencing defective mitoses via the activation of specific cell cycle checkpoints, regulated cell death pathways and/or cell senescence. This prevents the accumulation of karyotypic aberrations, which otherwise may drive oncogenesis and tumor progression. Here, we summarize experimental evidence confirming the role of caspase 2 (CASP2) as the main executor of mitotic catastrophe, and we discuss the signals that activate CASP2 in the presence of mitotic aberrations. In addition, we summarize the main p53-dependent and -independent effector pathways through which CASP2 limits chromosomal instability and non-diploidy, hence mediating robust oncosuppressive functions.

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“…4C) in response to DNA damage and mitotic checkpoint activation. A role for p53 in limiting the proliferation of polyploid cells has long been recognized (Ganem et al, 2014), and in human keratinocytes its inactivation further potentiates squamous differentiation . To test if p53 has a similar role in the context of Clasp2 deficiency, we knocked down Clasp2 expression in p53-null mouse keratinocytes (Fig.…”

Section: Clasp2 Expression Ensures Mitotic Fidelity In Primary Mouse mentioning

confidence: 99%

Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

Shahbazi¹,

Peña-Jiménez²,

Antonucci³

et al. 2017

Development

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Epidermal homeostasis is tightly controlled by a balancing act of selfrenewal or terminal differentiation of proliferating basal keratinocytes. An increase in DNA content as a consequence of a mitotic block is a recognized mechanism underlying keratinocyte differentiation, but the molecular mechanisms involved in this process are not yet fully understood. Using cultured primary keratinocytes, here we report that the expression of the mammalian microtubule and kinetochoreassociated protein Clasp2 is intimately associated with the basal proliferative makeup of keratinocytes, and its deficiency leads to premature differentiation. Clasp2-deficient keratinocytes exhibit increased centrosomal numbers and numerous mitotic alterations, including multipolar spindles and chromosomal misalignments that overall result in mitotic stress and a high DNA content. Such mitotic block prompts premature keratinocyte differentiation in a p53-dependent manner in the absence of cell death. Our findings reveal a new role for Clasp2 in governing keratinocyte undifferentiated features and highlight the presence of surveillance mechanisms that prevent cell cycle entry in cells that have alterations in the DNA content.

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Cytokinesis Failure Triggers Hippo Tumor Suppressor Pathway Activation

Cited by 330 publications

References 49 publications

Recurrent Micronucleation through Cell Cycle Progression in the Presence of Microtubule Inhibitors

Recurrent Micronucleation through Cell Cycle Progression in the Presence of Microtubule Inhibitors

Caspase 2 in mitotic catastrophe: The terminator of aneuploid and tetraploid cells

Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

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