Centromere-Associated Protein E: A Motor That Puts the Brakes on the Mitotic Checkpoint

Wood, Kenneth W.; Chua, Penelope; Sutton, David; Jackson, Jeffrey R.

doi:10.1158/1078-0432.ccr-07-4443

Cited by 44 publications

(29 citation statements)

References 38 publications

(40 reference statements)

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“…We cannot exclude the possibility that g-actin knockdown may have altered the localization and distribution of proteins such as centromereassociated protein E that binds to the kinetochore during mitosis and is essential for maintaining stable spindle-kinetochore attachment. 33 Defects in the localization and expression of kinetochore associated proteins may interefere with spindle-kinetochore binding. Moreover, correct spindle positioning is essential for proper mitotic progression and is regulated by retraction fibers, 34 cortex stiffness 35 and astral microtubules interactions with cortical actin.…”

Section: Discussionmentioning

confidence: 99%

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Po'uha

Kavallaris

2015

Cell Cycle

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Reorganization of the actin cytoskeleton during mitosis is crucial for regulating cell division. A functional role for g-actin in mitotic arrest induced by the microtubule-targeted agent, paclitaxel, has recently been demonstrated. We hypothesized that g-actin plays a role in mitosis. Herein, we investigated the effect of g-actin in mitosis and demonstrated that g-actin is important in the distribution of b-actin and formation of actin-rich retraction fibers during mitosis. The reduced ability of paclitaxel to induce mitotic arrest as a result of g-actin depletion was replicated with a range of mitotic inhibitors, suggesting that g-actin loss reduces the ability of broad classes of anti-mitotic agents to induce mitotic arrest. In addition, partial depletion of g-actin enhanced centrosome amplification in cancer cells and caused a significant delay in prometaphase/metaphase. This prolonged prometaphase/metaphase arrest was due to mitotic defects such as uncongressed and missegregated chromosomes, and correlated with an increased presence of mitotic spindle abnormalities in the g-actin depleted cells. Collectively, these results demonstrate a previously unknown role for g-actin in regulating centrosome function, chromosome alignment and maintenance of mitotic spindle integrity.

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Section: Discussionmentioning

confidence: 99%

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Po'uha

Kavallaris

2015

Cell Cycle

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“…cancer | checkpoint | kinesin | inhibitor | mitosis C entromere-associated protein-E (CENP-E; kinesin-7) is a kinetochore-associated kinesin motor protein with an essential and exclusive role in metaphase chromosome alignment and satisfaction of the mitotic checkpoint (1). CENP-E is a likely candidate to integrate the mechanics of kinetochore-microtubule interaction with the mitotic checkpoint signaling machinery responsible for restraining cell-cycle progression into anaphase.…”

mentioning

confidence: 99%

Antitumor activity of an allosteric inhibitor of centromere-associated protein-E

Wood

Lad²,

Luo³

et al. 2010

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

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208

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Centromere-associated protein-E (CENP-E) is a kinetochore-associated mitotic kinesin that is thought to function as the key receptor responsible for mitotic checkpoint signal transduction after interaction with spindle microtubules. We have identified GSK923295, an allosteric inhibitor of CENP-E kinesin motor ATPase activity, and mapped the inhibitor binding site to a region similar to that bound by loop-5 inhibitors of the kinesin KSP/Eg5. Unlike these KSP inhibitors, which block release of ADP and destabilize motor-microtubule interaction, GSK923295 inhibited release of inorganic phosphate and stabilized CENP-E motor domain interaction with microtubules. Inhibition of CENP-E motor activity in cultured cells and tumor xenografts caused failure of metaphase chromosome alignment and induced mitotic arrest, indicating that tight binding of CENP-E to microtubules is insufficient to satisfy the mitotic checkpoint. Consistent with genetic studies in mice suggesting that decreased CENP-E function can have a tumor-suppressive effect, inhibition of CENP-E induced tumor cell apoptosis and tumor regression.entromere-associated protein-E (CENP-E; kinesin-7) is a kinetochore-associated kinesin motor protein with an essential and exclusive role in metaphase chromosome alignment and satisfaction of the mitotic checkpoint (1). CENP-E is a likely candidate to integrate the mechanics of kinetochore-microtubule interaction with the mitotic checkpoint signaling machinery responsible for restraining cell-cycle progression into anaphase. CENP-E is a large dimeric protein consisting of an N-terminal kinesin motor domain tethered to a globular C-terminal domain through an extended coiled-coil rod domain (2, 3). The C-terminal, noncatalytic region of CENP-E is not only sufficient to specify localization to kinetochores, but it also mediates interaction of CENP-E with the serine/threonine kinase BubR1, a key effector of mitotic checkpoint signaling that forms complexes with the checkpoint proteins Cdc20, Bub3, and Mad2 to inhibit the ubiquitin ligase activity of the anaphase promoting complex APC/C CDC20 (4-7). The combined interaction of CENP-E with microtubules and a key regulator of APC/C CDC20 has led to the hypothesis that CENP-E functions as the key kinetochore microtubule receptor responsible for silencing mitotic checkpoint signal transduction after capture of spindle microtubules. This hypothesis was further strengthened by the finding that CENP-E could stimulate the kinase activity of BubR1 in a microtubule-sensitive manner (8, 9). In vitro, the addition of CENP-E to BubR1 resulted in a stimulation of BubR1 kinase activity. The addition of microtubules suppressed this stimulatory activity, an effect thought to be mediated by the CENP-E kinesin motor domain. Although the importance of CENP-E interaction with BubR1 and the role of BubR1-mediated phosphorylation in mitotic checkpoint function remain unclear, CENP-E remains a prominent candidate to play a key role in mitotic checkpoint signal transduction.Depletion of CENP-E from ...

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“…Allosteric CENPE inhibitor GSK923295 produces an antitumor activity in multiple cancer cell lines, several human tumor xenografts [5] while demonstrating a potency in a Phase I clinical trial [13]. Promising results of the GSK923295 clinical trial along with its mild side effects are the basis for further clinical studies of this drug.…”

Section: Introductionmentioning

confidence: 99%

“…Centromere-associated protein-E (CENP-E; kinesin-7) is a kinetochore-associated kinesin motor protein with an essential role in metaphase chromosome alignment and mitotic checkpoint [5]. Depletion of CENP-E by RNAi causes a prolonged cell-cycle delay in mitosis, characterized by an intact bipolar mitotic spindle with several chromosomes clustered close to spindle poles [6].…”

Section: Introductionmentioning

confidence: 99%

Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295

Tcherniuk

Oleinikov

2015

Cancer Letters

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Centromere-Associated Protein E: A Motor That Puts the Brakes on the Mitotic Checkpoint

Cited by 44 publications

References 38 publications

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Gamma-actin is involved in regulating centrosome function and mitotic progression in cancer cells

Antitumor activity of an allosteric inhibitor of centromere-associated protein-E

Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295

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