Causes and consequences of centrosome abnormalities in cancer

Godinho, Susana A.; Pellman, David

doi:10.1098/rstb.2013.0467

Cited by 304 publications

(350 citation statements)

References 143 publications

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“…This can be a consequence of genetic modifications, controlling the expression levels of proteins that are important for mitosis, or of the failure of a previous cell division. What drives such faulty divisions is not understood, although accumulation of extra centrosomes has been suggested as a possible cause 2,3,7 .…”

Section: Multipolar Divisionmentioning

confidence: 99%

“…A proper division process provides descendants with the correct amount of genetic material needed for subsequent cell growth and development, thus ensuring the continuation of the life cycle. Failure in the division process can lead to malfunctioning daughter cells that may give rise to cancer in multicellular organisms 2,3 . A key role in mitosis is played by the spindle, a self-organized subcellular structure composed of microtubules that segregates chromosomes during the division process and has been previously described as an active nematic gel.…”

Section: Ates 1 Introductionmentioning

confidence: 99%

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Defect driven shapes in nematic droplets: analogies with cell division

et al. 2017

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Building on the striking similarity between the structure of the spindle during mitosis in living cells and nematic textures in confined liquid crystals, we use a continuum model of two-dimensional nematic liquid crystal droplets, to examine the physical aspects of cell division. The model investigates the interplay between bulk elasticity of the microtubule assembly, described as a nematic liquid crystal, and surface elasticity of the cell cortex, modelled as a bounding flexible membrane, in controlling cell shape and division. The centrosomes at the spindle poles correspond to the cores of the topological defects required to accommodate nematic order in a closed geometry. We map out the progression of both healthy bipolar and faulty multi-polar division as a function of an effective parameter that incorporates active processes and controls centrosome separation. A robust prediction, independent of energetic considerations, is that the transition from a single cell to daughters cells occurs at critical value of this parameter. Our model additionally suggests that microtubule anchoring at the cell cortex may play an important role for successful bipolar division. This can be tested experimentally by regulating microtubule anchoring.Comment: 10 pages, 7 figure

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Section: Multipolar Divisionmentioning

confidence: 99%

Section: Ates 1 Introductionmentioning

confidence: 99%

Defect driven shapes in nematic droplets: analogies with cell division

et al. 2017

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“…Perturbing the centrosome integrity due to short centrioles or abnormal sized centrioles has been shown to affect the bipolar spindle assembly process (35,51), which can contribute to chromosome instability (15,58). Hence, we evaluated the physiological effects of CPAP loss as a consequence of centrobin depletion as well as excess CPAP due to overexpression of centrobin in a mitotic bipolar spindle assembly assay.…”

Section: Proteasome Inhibition Is Not Sufficient To Restore the Centrmentioning

confidence: 99%

Centrobin-mediated Regulation of the Centrosomal Protein 4.1-associated Protein (CPAP) Level Limits Centriole Length during Elongation Stage

Gudi

Haycraft

Bell

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism by which centriole dimensions are regulated is not understood. Results: The absence of centrobin leads to degradation of centrosomal protein 4.1-associated-protein (CPAP). High centrobin levels cause stabilization of CPAP and abnormal centrioles. Conclusion: Centrobin plays a role in the stability and centriole elongation function of CPAP and limits the centriole length. Significance: Identifying the regulatory mechanisms is crucial for understanding centriole biogenesis.

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“…In flies, centrosomal alterations have been found to expand the pool of proliferative progenitors in serial neuroblast transplantation assays, a phenomenon attributed to an imbalance in asymmetric divisions (14,15). In mammals, however, despite the strong correlation with hyperproliferative disorders, whether centrosomal abnormalities are the cause, the consequence, or a neutral bystander of cancer remains unclear (16,17).…”

mentioning

confidence: 99%

Epidermal development, growth control, and homeostasis in the face of centrosome amplification

Kulukian

Holland

Vitre

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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As nucleators of the mitotic spindle and primary cilium, centrosomes play crucial roles in equal segregation of DNA content to daughter cells, coordination of growth and differentiation, and transduction of homeostatic cues. Whereas the majority of mammalian cells carry no more than two centrosomes per cell, exceptions to this rule apply in certain specialized tissues and in select disease states, including cancer. Centrosome amplification, or the condition of having more than two centrosomes per cell, has been suggested to contribute to instability of chromosomes, imbalance in asymmetric divisions, and reorganization of tissue architecture; however, the degree to which these conditions are a direct cause of or simply a consequence of human disease is poorly understood. Here we addressed this issue by generating a mouse model inducing centrosome amplification in a naturally proliferative epithelial tissue by elevating Polo-like kinase 4 (Plk4) expression in the skin epidermis. By altering centrosome numbers, we observed multiciliated cells, spindle orientation errors, and chromosome segregation defects within developing epidermis. None of these defects was sufficient to impart a proliferative advantage within the tissue, however. Rather, impaired mitoses led to p53-mediated cell death and contributed to defective growth and stratification. Despite these abnormalities, mice remained viable and healthy, although epidermal cells with centrosome amplification were still appreciable. Moreover, these abnormalities were insufficient to disrupt homeostasis and initiate or enhance tumorigenesis, underscoring the powerful surveillance mechanisms in the skin.

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Causes and consequences of centrosome abnormalities in cancer

Cited by 304 publications

References 143 publications

Defect driven shapes in nematic droplets: analogies with cell division

Defect driven shapes in nematic droplets: analogies with cell division

Centrobin-mediated Regulation of the Centrosomal Protein 4.1-associated Protein (CPAP) Level Limits Centriole Length during Elongation Stage

Epidermal development, growth control, and homeostasis in the face of centrosome amplification

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