Centrosome control of the cell cycle

Doxsey, Stephen; Zimmerman, Wendy; Mikule, Keith

doi:10.1016/j.tcb.2005.04.008

Cited by 286 publications

(310 citation statements)

References 52 publications

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“…(Waldman et al, 1996). Since p53 responds to oncogenic stresses such as cyclin E deregulation (Deffie et al, 1995;Stewart et al, 1999), unscheduled DNA replication (Bartkova et al, 2005) or microtubule disruption (Doxsey et al, 2005), and has an essential role in the prevention of polyploidy (Di Leonardo et al, 1997;Aylon et al, 2006), it was important to verify the functionality of p53 in HCT116 Fbw7 À/À cells. We measured the level and activity of p53 by determining its own level and the levels of its target gene product, Mdm2, in Fbw7 À/À and Fbw7 þ / þ cells before and after treatment with vinblastine.…”

Section: Resultsmentioning

confidence: 99%

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

et al. 2008

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Fbw7 is a tumor suppressor that is mutated in numerous cancers. It encodes an E3 ubiquitin ligase, whose ability to decrease the levels of pivotal regulators of cell growth and proliferation underlies its tumor suppressor function. Here, we explore the consequences of Fbw7 inactivation on the outcome of chemotherapeutic treatments. When exposed to spindle toxins such as vinblastine and taxol, Fbw7-deficient cells undergo extensive mitotic slippage and endoreduplication, rendering them polyploid. A combined deregulation of several Fbw7 target proteins is required for this phenotype. Specifically, elevated expression of cyclin E and Aurora A in Fbw7-deficient cells is required for drug-induced polyploidy. However, overexpression of either cyclin E or Aurora A alone is not sufficient for drug-induced polyploidy. In addition, we demonstrate that Fbw7 deficiency limits the ability of p53 to respond to mitotic toxins but not to DNA damage. Furthermore, Fbw7 expression regulates the p53-dependent induction of genes such as Lats2 and p21 in response to vinblastine. Hence, we suggest that Fbw7 serves as a master regulator of the mitotic and tetraploidy checkpoints.

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Section: Resultsmentioning

confidence: 99%

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

et al. 2008

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“…The centrosome is the cytoplasmic structure responsible for organizing the mitotic microtubule network, and regulates various cell cycle transitions including G 1 /S, G 2 /mitosis, and metaphase-anaphase (reviewed in Doxsey et al 38 ). During mitosis, changes in cyclin B and Cdk1 phosphorylation during prophase have been found to originate at the centrosome.…”

Section: Discussionmentioning

confidence: 99%

Mitotic crisis: The unmasking of a novel role for RPA

Anantha

Borowiec

2009

Cell Cycle

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“…Centrosome amplification and aneuploidy are common events triggered by the loss of tumor suppressors or by overexpression of oncogenes. The accuracy of centrosome duplication is therefore essential for maintenance of genomic stability and centrosome duplication is coupled to the cell division cycle (D'Assoro et al, 2002;Doxsey et al, 2005;Fukasawa 2005;Sluder 2005;Nigg 2006; Tsou and Stearns, 2006).…”

Section: Introductionmentioning

confidence: 99%

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

et al. 2007

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The potential tumor suppressor antizyme and its endogenous inhibitor (antizyme inhibitor, AZI) have been implicated in the ubiquitin-independent proteasomal degradation of proteins involved in cell proliferation as well as in the regulation of polyamine levels. We show here that both antizyme and AZI concentrate at centrosomes and that antizyme preferentially associates with the maternal centriole. Interestingly, alterations in the levels of these proteins have opposing effects on centrosomes. Depletion of antizyme in various cell lines and primary cells leads to centrosome overduplication, whereas overexpression of antizyme reduces numerical centrosome abnormalities. Conversely, silencing of the antizyme inhibitor, AZI, results in a decrease of numerical centrosome abnormalities, whereas overexpression of AZI leads to centrosome overduplication. We further show that the numerical centrosome abnormalities are due to daughter centriole amplification. In summary, our results demonstrate that alterations in the antizyme/AZI balance cause numerical centrosomal defects and suggest a role for ubiquitin-independent proteasomal degradation in centrosome duplication.

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Centrosome control of the cell cycle

Cited by 286 publications

References 52 publications

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

Mitotic crisis: The unmasking of a novel role for RPA

Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

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