Polo-like kinase 4 controls centriole duplication but does not directly regulate cytokinesis

Holland, Andrew J.; Fachinetti, Daniele; Cruz, Sandrine Da; Zhu, Quan; Vitre, Benjamin; Lince-Faria, Mariana; Chen, Denaly; Parish, Nicole M.; Verma, Inder M.; Bettencourt-Dias, Mónica; Cleveland, Don W.

doi:10.1091/mbc.e11-12-1043

Cited by 37 publications

(39 citation statements)

References 30 publications

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“…Both centrosome amplification (37,38) and centrosome loss (39,40) have previously been reported to lead to a p53-dependent cell cycle arrest in skin fibroblasts. Centrosome amplification is also selected against during brain development in mice (16) and in Drosophila (12).…”

Section: Discussionmentioning

confidence: 99%

Chronic centrosome amplification without tumorigenesis

Vitre

Holland

Kulukian

et al. 2015

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

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Centrosomes are microtubule-organizing centers that facilitate bipolar mitotic spindle assembly and chromosome segregation. Recognizing that centrosome amplification is a common feature of aneuploid cancer cells, we tested whether supernumerary centrosomes are sufficient to drive tumor development. To do this, we constructed and analyzed mice in which centrosome amplification can be induced by a Cre-recombinase–mediated increase in expression of Polo-like kinase 4 (Plk4). Elevated Plk4 in mouse fibroblasts produced supernumerary centrosomes and enhanced the expected mitotic errors, but proliferation continued only after inactivation of the p53 tumor suppressor. Increasing Plk4 levels in mice with functional p53 produced centrosome amplification in liver and skin, but this did not promote spontaneous tumor development in these tissues or enhance the growth of chemically induced skin tumors. In the absence of p53, Plk4 overexpression generated widespread centrosome amplification, but did not drive additional tumors or affect development of the fatal thymic lymphomas that arise in animals lacking p53. We conclude that, independent of p53 status, supernumerary centrosomes are not sufficient to drive tumor formation.

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Section: Discussionmentioning

confidence: 99%

Chronic centrosome amplification without tumorigenesis

Vitre

Holland

Kulukian

et al. 2015

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

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“…Cell culture and flow cytometry were performed as previously described (38). osTIR1-9Myc was introduced into Flp-In TRex-DLD-1 parental cells or into RPE1 cells using retroviral delivery as described previously (39).…”

Section: Methodsmentioning

confidence: 99%

Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells

Holland

Fachinetti

Han

et al. 2012

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

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303

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Inducible degradation is a powerful approach for identifying the function of a specific protein or protein complex. Recently, a plant auxin-inducible degron (AID) system has been shown to degrade AID-tagged target proteins in nonplant cells. Here, we demonstrate that an AID-tagged protein can functionally replace an endogenous protein depleted by RNAi, leading to an inducible null phenotype rapidly after auxin addition. The AID system is shown to be capable of controlling the stability of AID-tagged proteins that are in either nuclear or cytoplasmic compartments and even when incorporated into protein complexes. Induced degradation occurs rapidly after addition of auxin with protein half-life reduced to as little as 9 min and proceeding to completion with firstorder kinetics. AID-mediated instability is demonstrated to be rapidly reversible. Induced degradation is shown to initiate and continue in all cell cycle phases, including mitosis, making this system especially useful for identifying the function(s) of proteins of interest during specific points in the mammalian cell cycle.proteasome | SCF | ubiquitin

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“…The expression levels of Plk4 continue to rise and peak in mitosis, when it facilitates late mitotic progression [24]. During cytokinesis, Plk4 localizes to the midbody where it may assist in proper cleavage furrow positioning, though this remains controversial [24][25][26]. Overexpression of Plk4 results in supernumerary centrosomes and multipolar spindle formation, highlighting the importance of this kinase in centrosome regulation [23,[27][28][29].…”

Section: The Plk Family: Expression Localization and Cellular Functmentioning

confidence: 99%

Polo-Like Kinases in Colorectal Cancer: Potential for Targeted Therapy

Kazazian

Brashavitskaya

Zih

et al. 2015

Curr Colorectal Cancer Rep

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The five individual members of the mammalian polo-like kinase family play non-redundant roles in centriole replication and maturation, mitotic progression, cytokinesis, and the DNA damage response. In human colorectal cancer, Plk1 and Plk4 are expressed at higher levels in tumor than adjacent normal mucosa, and the degree of overexpression correlates with adverse prognosis. In colorectal cancer cell lines, suppression of Plk1 activity leads to mitotic arrest and apoptosis, while inhibition of Plk4 activity reduces tumor growth and invasion. Inhibition of Plk1 or Plk4 in mice using orally bioavailable agents reduces the growth of human colorectal cancer xenografts. On the basis of these preclinical studies, clinical trials of several different targeted anti-Plk1 agents have been undertaken in patients with advanced solid tumors, and a phase I trial of the anti-Plk4 inhibitor CFI-400945 is currently accruing. Here, we review the rationale, results, and potential limitations of Plks as therapeutic targets. Evidence from genetic mouse models suggests that Plk1, Plk2, Plk3, and Plk4 may all possess tumor suppressive activity, particularly with aging. Thus, enthusiasm for the use of targeted Plk inhibitors in cancer therapy must be tempered somewhat by the potential for development of second primary tumors in the long term.

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Polo-like kinase 4 controls centriole duplication but does not directly regulate cytokinesis

Cited by 37 publications

References 30 publications

Chronic centrosome amplification without tumorigenesis

Chronic centrosome amplification without tumorigenesis

Inducible, reversible system for the rapid and complete degradation of proteins in mammalian cells

Polo-Like Kinases in Colorectal Cancer: Potential for Targeted Therapy

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