Mechanisms of Chromosomal Instability

Thompson, Sarah L.; Bakhoum, Samuel F.; Compton, Duane A.

doi:10.1016/j.cub.2010.01.034

Cited by 522 publications

(503 citation statements)

References 134 publications

(196 reference statements)

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“…Our data also show that Cep70 is necessary for the organization and orientation of the mitotic spindle, which is consistent with the function of the centrosome as the driving force for bipolar spindle assembly in animal cells (3,4). Given that deregulation of the mitotic spindle is associated with genomic instability, which may lead to tumorigenesis and malignant transformation (21), further studies are warranted to examine whether abnormal expression of Cep70 is involved in the development of cancer.…”

Section: Cep70 Plays a Significant Role In The Organization Of Both Pmentioning

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CEP70 Protein Interacts with γ-Tubulin to Localize at the Centrosome and Is Critical for Mitotic Spindle Assembly

Shi

Sun

Liu

et al. 2011

Journal of Biological Chemistry

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Deregulation of the mitotic spindle has been implicated in genomic instability, an important aspect of tumorigenesis and malignant transformation. To ensure the fidelity of chromosome transmission, the mitotic spindle is assembled by exquisite mechanisms and orchestrated by centrosomes in animal cells. Centrosomal proteins especially are thought to act coordinately to ensure accurate spindle formation, but the molecular details remain to be investigated. In this study, we report the molecular characterization and functional analysis of a novel centrosomal protein, Cep70. Our data show that Cep70 localizes to the centrosome throughout the cell cycle and binds to the key centrosomal component, ␥-tubulin, through the peptide fragments that contain the coiled-coil domains. Our data further reveal that the centrosomal localization pattern of Cep70 is dependent on its interaction with ␥-tubulin. Strikingly, Cep70 plays a significant role in the organization of both preexisting and nascent microtubules in interphase cells. In addition, Cep70 is necessary for the organization and orientation of the bipolar spindle during mitosis. These results thus report for the first time the identification of Cep70 as an important centrosomal protein that interacts with ␥-tubulin and underscore its critical role in the regulation of mitotic spindle assembly.

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Section: Cep70 Plays a Significant Role In The Organization Of Both Pmentioning

(Expert classified)

CEP70 Protein Interacts with γ-Tubulin to Localize at the Centrosome and Is Critical for Mitotic Spindle Assembly

Shi

Sun

Liu

et al. 2011

Journal of Biological Chemistry

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“…Independent of the spindle checkpoint function, Mad2 overexpression might cause CIN by interfering with kinetochore- microtubule (k-MT) dynamics (28,29). Formation of proper k-MT attachments requires a finely tuned balance between stabilizing factors and destabilizing factors (30).…”

Section: Discussionmentioning

confidence: 99%

Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

Bian

Kitagawa

Bansal

et al. 2014

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

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Significance The spindle checkpoint is required for proper chromosome segregation. Mitotic arrest deficiency 2 (Mad2), a component of the spindle checkpoint, is overexpressed in many cancer cells. This phenotype can be used to specifically kill Mad2-overexpressing tumor cells. Because the spindle checkpoint pathway is highly conserved between yeast and humans, we performed a screen to identify mutants in which Mad2 overexpression kills yeast cells. The screen revealed that Mad2 overexpression induced lethality in 13 gene deletions. Among the human homologs of the 13 candidate genes, a gene encoding protein phosphatase 2 (PP2A) significantly inhibited the growth of Mad2-overexpressing tumor cells. These results indicate that PP2A can be a specific therapeutic target in Mad2-overexpressing tumors.

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“…This feature correlates strongly with chromosomal instability (CIN), karyotypic heterogeneity, and other malignant phenotypes. 3,4 Supernumerary centrosomes can prove lethal by inducing spindle multipolarity with subsequent anaphase catastrophe 5 or multipolar mitosis. [6][7][8] Much evidence now supports a causative link between CIN and malignant transformation, particularly in multi-step carcinogenesis.…”

Section: Open Questionsmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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Mechanisms of Chromosomal Instability

Cited by 522 publications

References 134 publications

CEP70 Protein Interacts with γ-Tubulin to Localize at the Centrosome and Is Critical for Mitotic Spindle Assembly

CEP70 Protein Interacts with γ-Tubulin to Localize at the Centrosome and Is Critical for Mitotic Spindle Assembly

Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

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