Exit from mitosis requires the proteolytic degradation of mitotic cyclins, which is instigated by the APC/C ubiquitin ligase. The coincidence of mitotic cyclin B1 degradation with the onset of anaphase intuitively suggested a requirement of cyclin degradation for sister chromatid separation. While this hypothesis has originally been refuted, evidence that cyclin B1 degradation is required for anaphase during meiosis has been obtained, while its requirement for anaphase during mitosis is still more controversial. By studying human cells engineered to express nondegradable cyclin B1, we have recently shown that stable cyclin B1 affects progression through mitosis at various steps in a dose-dependent manner. These experiments suggest that controlled exit from mitosis might involve CDK activity thresholds for important late mitotic events, such as the onset of anaphase, formation of the spindle midzone, the onset of cytokinesis, cellular abscission and chromosome decondensation.
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Pharmaceuticals (Basel)
December 2024
Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria, 09042 Monserrato, Italy.
The primary method used to pharmacologically arrest cancer development and its metastasis is to disrupt the cell division process. There are a few approaches that may be used to meet this objective, mainly through inhibiting DNA replication or mitosis. Despite intensive studies on new chemotherapeutics, the biggest problem remains the side effects associated with the inhibition of cell division in non-tumoural host cells.
View Article and Find Full Text PDFJ Biol Chem
January 2025
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA. Electronic address:
Selective inhibitors that target cyclin dependent kinases 4 and 6 (CDK4/6i) are FDA approved for treatment of a subset of breast cancers and are being evaluated in numerous clinical trials for other cancers. Despite this advance, a subset of tumors are intrinsically resistant to these drugs and acquired resistance is nearly inevitable. Recent mechanistic evidence suggests that in addition to stalling the cell cycle, the anti-tumor effects of CDK4/6i involve the induction of chromosomal instability (CIN).
View Article and Find Full Text PDFCurr Biol
January 2025
Department of Cell Biology, Duke University Medical Center, Durham, NC 27705, USA; Duke Center for Quantitative Living Systems, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:
Anaphase is tightly controlled spatiotemporally to ensure proper separation of chromosomes. The mitotic spindle, the self-organized microtubule structure driving chromosome segregation, scales in size with the available cytoplasm. Yet, the relationship between spindle size and chromosome movement remains poorly understood.
View Article and Find Full Text PDFNat Cell Biol
January 2025
CNRS UMR144 - UMR3664, Institut Curie, Sorbonne Université, PSL Research University, Paris, France.
Errors during cell division lead to aneuploidy, which is associated with genomic instability and cell transformation. In response to aneuploidy, cells activate the tumour suppressor p53 to elicit a surveillance mechanism that halts proliferation and promotes senescence. The molecular sensors that trigger this checkpoint are unclear.
View Article and Find Full Text PDFCell Death Dis
January 2025
Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia.
Polyploidy is a common outcome of chemotherapies, but there is conflicting evidence as to whether polyploidy is an adverse, benign or even favourable outcome. We show Aurora B kinase inhibitors efficiently promote polyploidy in many cell types, resulting in the cell cycle exit in RB and p53 functional cells, but hyper-polyploidy in cells with loss of RB and p53 function. These hyper-polyploid cells (>8n DNA content) are viable but have lost long-term proliferative potential in vitro and fail to form tumours in vivo.
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