For example, chromosomes condense into a rod-like shape, centrosomes, and migrate over several microns to properly position in the cell, and cytoskeletal actin and microtubules organize into structures that segregate chromosomes and divide the cell into two. Cell division thus involves a precise control over numerous types and numbers of molecular activities in space, and individual division steps are tightly coordinated in time.
The driving forces of cell division
Understand the mechanisms behind this dynamic yet highly-ordered process requires the integration of molecular, cell biological, biophysical, structural, engineering, and biochemical studies. In this Research Topic, we aim to bring together researchers investigating mechanisms of cell division using various model systems and employing diverse experimental and theoretical approaches.
Our primary focus will be on the architecture, mechanics, and dynamics of cell division, but will not be limited to only these aspects. Article types can be either Original Research or Reviews. We believe that this topic will enable the community to share the most up-to-date views on cell division, and lead to new ideas which will help to understand this essential cellular process. Keywords : microtubules, actin, forces, microscopy, mitosis, meiosis, spindles, abscission, contractile ring, cytokinesis, motor proteins.
Important Note : All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review. With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area!
Find out more on how to host your own Frontiers Research Topic or contribute to one as an author. Manuscripts can be submitted to this Research Topic via the following journals:. Cdk1-cyclinB1 mediates the inactivation of caspases, potentially counteracting the pro-death signaling resulting from MOMP and cytochrome c release. The mitochondrial fission mediator Drp1 appears to antagonize Cdk1-cyclinB1by promoting slippage while the elevated ROS level correlates with higher Cdk1-cyclinB1 activity favoring a sustained mitotic arrest.
Thus, the fate of a mitotically arrested cell is determined by the complex interactions between various regulatory modules. Many studies on mitotic cell death have focused extensively on the mitotic control of anti-apoptotic and pro-apoptotic proteins. Mitochondria normally form an tubular network during interphase; however, they undergo extensive fission during mitosis.
Regulation of mitochondrial fission is mediated by Drp1 Dynamin-related protein 1 which is recruited by Fis1, Mff, MiD49 and MiD51 mitochondrial dynamics proteins of 49 and 51 kDa at the mitochondrial outer membrane, while fusion is mediated by mitofusins Mfn1 and Mfn2 located at the outer mitochondrial membrane and by Opa1 located at the inner mitochondrial membrane. Hence, the role of the mitochondrial fission in the modulation of mitotic cell death requires a careful examination.
While MOMP is critical for induction of cell death, weak MOMP with limited activation of caspase is not sufficient for inducing cell death and instead results in genomic instability and tumorigenesis Ichim et al. This has raised the question whether tipping of the balance in favor of pro-apoptotic proteins during prolonged mitosis is sufficient to trigger cell death.
Cell and tissue mechanics: the new cell biology frontier
Interestingly, an amino-terminally truncated isoform of Mcl-1, in addition to its role in sequestering anti-apoptotic proteins during interphase, can localize to mitochondrial matrix to facilitate mitochondrial functions Perciavalle et al. Whether this Mcl-1 isoform affects mitochondrial functions such as ATP production, maintenance of mitochondrial fusion and cristae structures and if these effects do impinge on the regulation of mitotic cell death require further investigations.
Anti-mitotic agents that alter spindle-kinetochore attachment dynamics lead to the activation of SAC, which then prevents both the onset of anaphase and mitotic exit, thus causing cells to arrest in prometaphase. It is known that cells are unable to maintain the high Cdk1 activity-status indefinitely due to slow erosion of cyclin B1 levels despite the active checkpoint Brito and Rieder, Given these diverse regulations at play, cells can adopt two different fates following the checkpoint-imposed prolonged arrest: mitotic cell death or mitotic slippage.
Substantial efforts have been made to map the complex signaling network regulating the mitotic cell death. Early studies had proposed a competing-networks model according to which the pathways mediating mitotic slippage measured by the decline in cyclin B1 level and the mitotic cell death quantified by the pro-death signals are mechanistically independent. The activity thresholds and stochastic competition between the two pathways dictate the final cell fates during an extended mitotic arrest Gascoigne and Taylor, ; Huang et al.
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Based on the observation that the time span of mitosis does not correlate with cell fate, this model marks cyclin B-Cdk1 as the key element that controls both slippage and apoptosis Gascoigne and Taylor, ; Brito and Rieder, With this notion in view, a new strategy that inhibits cytokinesis independently of SAC, for instance by targeting PRC1 protein regulator of cytokinesis 1 , has been used to enhance the lethal effects of anti-mitotic agents Liu et al. Such a network may potentially include feedback mechanisms originating from mitochondria regulatory machinery or the apoptotic signaling modules and converging onto the checkpoint control.
A genome-wide siRNA screen has indicated a potential role for Drp1 in promoting mitotic slippage and in generating ROS via mitochondrial fragmentation. While new evidence is emerging to help further dissection of SAC silencing, it is useful to consider therapeutic benefits of impairing SAC silencing to enhance mitotic cell death. Disruption of SAC-silencing would not only prolong mitotic arrest and enhance MOMP, but may also engender other cellular disparities, such as cohesion fatigue and cell fate alterations, that are detrimental to the survival of the mitotically arrested tumor cells Rieder and Maiato, ; Daum et al.
Hence, targeting the SAC silencing machinery may provide a new strategy for the development of the next generation of anti-mitotic agents for combinatorial therapies. The mitotic cell death is governed by a complex network that coordinates SAC activation and silencing, levels of cyclin B1-Cdk1 activity, balance between pro- and anti-apoptotic proteins, extent of MOMP, mitochondrial morphology and caspase activation.
WR wrote some sections of the manuscript. HL wrote some parts of the manuscript. US wrote and edited the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The U. National Center for Biotechnology Information , U.
Front Cell Dev Biol. Published online Jan Author information Article notes Copyright and License information Disclaimer. Received Aug 10; Accepted Dec The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Abstract Targeting the mitotic pathways of rapidly proliferating tumor cells has been an effective strategy in traditional cancer therapy. Keywords: mitosis, mitotic checkpoint, mitochondria, apoptosis, mitotic death. Introduction Mitosis M phase is characterized by a set of highly orchestrated cellular events. Open in a separate window. Mitochondrial Dynamics and Functions During Prolonged Mitosis Many studies on mitotic cell death have focused extensively on the mitotic control of anti-apoptotic and pro-apoptotic proteins.
Mapping the Mitotic Cell Death Signaling Network Anti-mitotic agents that alter spindle-kinetochore attachment dynamics lead to the activation of SAC, which then prevents both the onset of anaphase and mitotic exit, thus causing cells to arrest in prometaphase. Conclusion The mitotic cell death is governed by a complex network that coordinates SAC activation and silencing, levels of cyclin B1-Cdk1 activity, balance between pro- and anti-apoptotic proteins, extent of MOMP, mitochondrial morphology and caspase activation.
Author Contributions WR wrote some sections of the manuscript. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Footnotes Funding. References Allan L. Cell 26 — Paclitaxel targets mitochondria upstream of caspase activation in intact human neuroblastoma cells. FEBS Lett. Hydrogen peroxide prolongs mitotic arrest in a dose dependent manner and independently of the spindle assembly checkpoint activity in Saccharomyces cerevisiae.
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Mitosis-targeted anti-cancer therapies: where they stand. Cell Death Dis. Epigenetic dysregulation of the Drp1 binding partners MiD49 and MiD51 increases mitotic mitochondrial fission and promotes pulmonary arterial hypertension: mechanistic and therapeutic implications. Circulation — Castration-resistant prostate cancer: AUA guideline amendment.
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Cohesion fatigue induces chromatid separation in cells delayed at metaphase. Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study.
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Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation. EMBO J. Cell Res. Targeting mitosis in cancer: emerging strategies.
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Cell 60 — Management of treatment-related toxicity in advanced ovarian cancer. Oncologist 7 11— Critical role of anti-apoptotic Bcl-2 protein phosphorylation in mitotic death. PP2A-B56 opposes Mps1 phosphorylation of Knl1 and thereby promotes spindle assembly checkpoint silencing.