A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase

Gromley, Adam; Jurczyk, Agata; Sillibourne, James; Halilovic, Ensar; Mogensen, Mette; Groisman, Irina; Blomberg, Maureen; Doxsey, Stephen

doi:10.1083/jcb.200301105

Cited by 246 publications

(267 citation statements)

References 52 publications

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“…Under these conditions, cells can still achieve the mitotic division, but then arrest in the following G1 (Casenghi et al, 1999;Ciciarello et al, 2001). Interestingly, a similar phenotype has been described after physical centrosome ablation in S or G2 phases (Hinchcliffe et al, 2001;Khodjakov and Rieder, 2001), or inactivation of centrosomal components by RNA interference (Gromley et al, 2003). In these instances, mitosis progression is not affected per se, but cells cannot undergo further replication and are arrested in the following G1 phase.…”

Section: Discussionmentioning

confidence: 63%

p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation

Tritarelli

Oricchio

Ciciarello

et al. 2004

MBoC

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We recently demonstrated that the p53 oncosuppressor associates to centrosomes in mitosis and this association is disrupted by treatments with microtubule-depolymerizing agents. Here, we show that ATM, an upstream activator of p53 after DNA damage, is essential for p53 centrosomal localization and is required for the activation of the postmitotic checkpoint after spindle disruption. In mitosis, p53 failed to associate with centrosomes in two ATM-deficient, ataxiatelangiectasia-derived cell lines. Wild-type ATM gene transfer reestablished the centrosomal localization of p53 in these cells. Furthermore, wild-type p53 protein, but not the p53-S15A mutant, not phosphorylatable by ATM, localized at centrosomes when expressed in p53-null K562 cells. Finally, Ser15 phosphorylation of endogenous p53 was detected at centrosomes upon treatment with phosphatase inhibitors, suggesting that a p53 dephosphorylation step at centrosome contributes to sustain the cell cycle program in cells with normal mitotic spindles. When dissociated from centrosomes by treatments with spindle inhibitors, p53 remained phosphorylated at Ser15. AT cells, which are unable to phosphorylate p53, did not undergo postmitotic proliferation arrest after nocodazole block and release. These data demonstrate that ATM is required for p53 localization at centrosome and support the existence of a surveillance mechanism for inhibiting DNA reduplication downstream of the spindle assembly checkpoint

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Section: Discussionmentioning

confidence: 63%

p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation

Tritarelli

Oricchio

Ciciarello

et al. 2004

MBoC

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“…Alteration of centrosomal components that results in inhibition of cytokinesis and centrosome duplication has been shown to induce cell cycle arrest [74,75,100]. Both loss and overexpression of centriolin, a newly identified centrosomal component, induces cytokinetic defects and a G 1 -phase cell cycle arrest [100]. Moreover, disruption of AKAP450 localization to centrosomes results in centrosomal and cytokinetic defects leading to a p53 dependent G 1 -phase cell cycle arrest [74].…”

Section: Discussionmentioning

confidence: 99%

“…The growth arrest response in cells lacking centrosomes could be due to a loss of key components, whereas multiple centrosomes could provide an imbalance of these components or simply lead to improper spindle alignment, unequal partition of chromosomal DNA and a DNA damage response [37,40,50]. Alteration of centrosomal components that results in inhibition of cytokinesis and centrosome duplication has been shown to induce cell cycle arrest [74,75,100]. Both loss and overexpression of centriolin, a newly identified centrosomal component, induces cytokinetic defects and a G 1 -phase cell cycle arrest [100].…”

Section: Discussionmentioning

confidence: 99%

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest

Don

Dallapiazza

Bennin

et al. 2006

Experimental Cell Research

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Cyclin G2 is an atypical cyclin that associates with active protein phosphatase 2A. Cyclin G2 gene expression correlates with cell cycle inhibition; it is significantly upregulated in response to DNA damage and diverse growth inhibitory stimuli, but repressed by mitogenic signals. Ectopic expression of cyclin G2 promotes cell cycle arrest, cyclin dependent kinase 2 inhibition, and the formation of aberrant nuclei [1]. Here we report that endogenous cyclin G2 copurifies with centrosomes and microtubules (MT), and that ectopic G2 expression alters microtubule stability. We find exogenous and endogenous cyclin G2 present at microtubule organizing centers (MTOCs) where it colocalizes with centrosomal markers in a variety of cell lines. We previously reported that cyclin G2 forms complexes with active protein phosphatase 2A (PP2A) and colocalizes with PP2A in a detergent resistant compartment. We now show that cyclin G2 and PP2A colocalize at MTOCs in transfected cells, and that the endogenous proteins copurify with isolated centrosomes. Displacement of the endogenous centrosomal scaffolding protein AKAP450 that anchors PP2A at the centrosome, resulted in the depletion of centrosomal cyclin G2. We find that ectopic expression of cyclin G2 induces microtubule bundling and resistance to depolymerization, inhibition of polymer regrowth from MTOCs, and a p53 dependent cell cycle arrest. Furthermore, we determined that a 100 amino acid carboxy-terminal region of cyclin G2 is sufficient to both direct GFP localization to centrosomes and induce cell cycle inhibition. Colocalization of endogenous cyclin G2 with only one of two GFPcentrin tagged centrioles, the mature centriole present at microtubule foci, indicate that cyclin G2 resides primarily on the mother centriole. Copurification of cyclin G2 and PP2A subunits with microtubules and centrosomes, together with the effects of ectopic cyclin G2 on cell cycle progression, nuclear morphology, and microtubule growth and stability, suggests that cyclin G2 may modulate the cell cycle and cellular division processes through modulation of PP2A and centrosomal associated activities.

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“…Direct yeast two-hybrid interactions were performed essentially as described previously (Gromley et al, 2003). Pericentrin, ␥ tubulin, GCP2, and GCP3 coding sequences were amplified from plasmid DNA by PCR by using Pfu Turbo (Stratagene, La Jolla, CA), cloned into either pGBKT7 or pGADT7 (BD Biosciences Clontech, Palo Alto, CA) and completely sequenced.…”

Section: Yeast Two-hybrid Cloning/methodsmentioning

confidence: 99%

Mitosis-specific Anchoring of γ Tubulin Complexes by Pericentrin Controls Spindle Organization and Mitotic Entry

Zimmerman

Sillibourne

Rosa

et al. 2004

MBoC

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258

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Microtubule nucleation is the best known function of centrosomes. Centrosomal microtubule nucleation is mediated primarily by ␥ tubulin ring complexes (␥ TuRCs). However, little is known about the molecules that anchor these complexes to centrosomes. In this study, we show that the centrosomal coiled-coil protein pericentrin anchors ␥ TuRCs at spindle poles through an interaction with ␥ tubulin complex proteins 2 and 3 (GCP2/3). Pericentrin silencing by small interfering RNAs in somatic cells disrupted ␥ tubulin localization and spindle organization in mitosis but had no effect on ␥ tubulin localization or microtubule organization in interphase cells. Similarly, overexpression of the GCP2/3 binding domain of pericentrin disrupted the endogenous pericentrin-␥ TuRC interaction and perturbed astral microtubules and spindle bipolarity. When added to Xenopus mitotic extracts, this domain uncoupled ␥ TuRCs from centrosomes, inhibited microtubule aster assembly, and induced rapid disassembly of preassembled asters. All phenotypes were significantly reduced in a pericentrin mutant with diminished GCP2/3 binding and were specific for mitotic centrosomal asters as we observed little effect on interphase asters or on asters assembled by the Ran-mediated centrosome-independent pathway. Additionally, pericentrin silencing or overexpression induced G2/antephase arrest followed by apoptosis in many but not all cell types. We conclude that pericentrin anchoring of ␥ tubulin complexes at centrosomes in mitotic cells is required for proper spindle organization and that loss of this anchoring mechanism elicits a checkpoint response that prevents mitotic entry and triggers apoptotic cell death. INTRODUCTIONThe centrosome is the primary microtubule-organizing center in animal cells. At the centrosome core is a pair of barrel-shaped microtubule assemblies, the centrioles (Doxsey, 2001). Centrioles are capable of self-assembly (Marshall et al., 2001;Khodjakov et al., 2002) and can serve as templates for recruitment and organization of the surrounding pericentriolar matrix (Bobinnec et al., 1998;Kirkham et al., 2003). The pericentriolar material or centrosome matrix contains a high proportion of coiled coil proteins and is the site of microtubule nucleation. Within the matrix are large protein complexes of ␥ tubulin and associated proteins that have a ring-like structure and mediate the nucleation of microtubules called ␥ tubulin ring complexes or ␥ TuRCs (Moritz et al., 1995a;Zheng et al., 1995). Other proteins may share the ability to nucleate microtubules because centrosomes can organize microtubules in the absence of functional ␥ tubulin (Sampaio et al., 2001;Strome et al., 2001;Hannak et al., 2002).During cell cycle progression, centrosomes "mature" by recruiting additional ␥ TuRCs and several other proteins, resulting in an increase in the nucleation capacity of the centrosome (reviewed in Blagden and Glover, 2003). However, we still know very little about proteins that directly anchor ␥ TuRCs to centrosomes in vertebrate cells. ...

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A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase

Cited by 246 publications

References 52 publications

p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation

p53 Localization at Centrosomes during Mitosis and Postmitotic Checkpoint Are ATM-dependent and Require Serine 15 Phosphorylation

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest

Mitosis-specific Anchoring of γ Tubulin Complexes by Pericentrin Controls Spindle Organization and Mitotic Entry

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