Mammalian RanBP1 regulates centrosome cohesion during mitosis

Fiore, Barbara; Ciciarello, Marilena; Mangiacasale, Rosamaria; Palena, Antonella; Tassin, Anne‐Marie; Cundari, Enrico; Lavia, Patrizia

doi:10.1242/jcs.00624

Cited by 78 publications

(71 citation statements)

References 50 publications

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“…Keryer et al, suggest that centrosomeassociated RanGTP could locally destabilize importin/centrosomal protein complexes and thus activate processes important for centrosome activities such as MT assembly, anchorage, and dynamics. Not only Ran, but also RanBP1 and Crm1, are stably present at centrosomes [106][107][108]. We hypothesize that regulation of CRM1-dependent export of G2 controls its functions and may impact an associated centrosomal process.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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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“…A previous study indicates that a proteinaceous linker between the pair of centrioles mediates their cohesion (Paintrand et al, 1992), though the identity of this linker remains unknown. Recent studies demonstrate that several proteins, including NIMA-related kinase 2 (Nek2), protein phosphatase 1 (PP1), C-Nap1, dynamin 2, and RanBP1, are involved in centriolar cohesion (Mayor et al, 2000;Meraldi and Nigg, 2001;Di Fiore et al, 2003;Thompson et al, 2004). Among these proteins, C-Nap1, also known as CEP250 (Mack et al, 1998), is a centrosomal protein and the presumed substrate of Nek2 and PP1 (Fry et al, 1998;Helps et al, 2000;Meraldi and Nigg, 2001).…”

Section: Introductionmentioning

confidence: 99%

Rootletin Interacts with C-Nap1 and May Function as a Physical Linker between the Pair of Centrioles/Basal Bodies in Cells

Yang

Adamian

2006

MBoC

142

174

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Rootletin, a major structural component of the ciliary rootlet, is located at the basal bodies and centrosomes in ciliated and nonciliated cells, respectively. Here we investigated its potential role in the linkage of basal bodies/centrioles and the mechanism involved in such linkages. We show that rootletin interacts with C-Nap1, a protein restricted at the ends of centrioles and functioning in centrosome cohesion in interphase cells. Their interaction in vivo is supported by their colocalization at the basal bodies/centrioles and coordinated association with the centrioles during the cell cycle. Ultrastructural examinations demonstrate that rootletin fibers connect the basal bodies in ciliated cells and are present both at the ends of and in between the pair of centrioles in nonciliated cells. The latter finding stands in contrast with C-Nap1, which is present only at the ends of the centrioles. Transient expression of C-Nap1 fragments dissociated rootletin fibers from the centrioles, resulting in centrosome separation in interphase. Overexpression of rootletin in cells caused multinucleation, micronucleation, and irregularity of nuclear shape and size, indicative of defects in chromosome separation. These data suggest that rootletin may function as a physical linker between the pair of basal bodies/centrioles by binding to C-Nap1.

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“…The bulk of RanGTP localizes to chromosomes, but Ran network components also localize at specific structures of the mitotic apparatus in somatic mitotic cells and modulate the activity of MT-regulatory factors therein (reviewed by Di Fiore et al, 2004). In particular, RanBP1 associates with the spindle MTs with an accumulation at spindle poles (Di Fiore et al, 2003), and therein colocalizes with a fraction of Ran and importin-b ; all three components are also present in purified mitotic MT preparations in cosedimentation assays (Tedeschi et al, 2007). Noteworthily, genes encoding Ran and its partners are increasingly found to be aberrantly expressed in transformed and cancer cells (also see Abe et al, 2008;Kurisetty et al, 2008;Rensen et al, 2008;Xia et al, 2008a and references therein).…”

Section: Introductionmentioning

confidence: 99%

“…It is transcriptionally regulated by the E2F/Rb pathway (Di Matteo et al, 1995;Di Fiore et al, 1999;Ishida et al, 2001) and is aberrantly expressed in many cancers (Rensen et al, 2008). To understand how high RanBP1 levels might affect cell transformation, we previously induced RanBP1 overexpression in cultured cells: this caused the formation of multipolar mitotic spindles (Guarguaglini et al, 2000;Di Fiore et al, 2003). Roles of RanBP1 in control of MT function also emerge from RNA interference (RNAi) experiments: RanBP1-downregulated cells assemble mitotic spindles that are apparently normal but have altered properties, including resistance to MT depolymerization induced by chemical or physical agents, failure to associate with cyclin B1 and abnormal recruitment of the MT-stabilizing factor HURP (hepatoma up-regulated protein, itself viewed as a potential oncogene).…”

Section: Introductionmentioning

confidence: 99%

RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner

et al. 2009

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Mitotic microtubule (MT)-targeting drugs are widely used to treat cancer. The GTPase Ran regulates multiple processes, including mitotic spindle assembly, spindle pole formation and MT dynamics; Ran activity is therefore essential to formation of a functional mitotic apparatus. The RanBP1 protein, which binds Ran and regulates its interaction with effectors, is overexpressed in many cancer types. Several observations indicate that RanBP1 contributes to regulate the function of the mitotic apparatus: RanBP1 inactivation yields hyperstable MTs and induces apoptosis during mitosis, reminiscent of the effects of the MT-stabilizing drug taxol. Here we have investigated the influence of RanBP1 on spontaneous and taxol-induced apoptosis in transformed cells. We report that RanBP1 downregulation by RNA interference activates apoptosis in several transformed cell lines regardless of their p53 status, but not in the caspase-3-defective MCF-7 breast cancer cell line. Furthermore, RanBP1-interfered cells show an increased apoptotic response to taxol compared to their counterpart with normal or high RanBP1 levels, and this response is caspase-3 dependent. These results indicate that RanBP1 can modulate the outcome of MT-targeting therapeutic protocols.

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Mammalian RanBP1 regulates centrosome cohesion during mitosis

Cited by 78 publications

References 50 publications

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

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

Rootletin Interacts with C-Nap1 and May Function as a Physical Linker between the Pair of Centrioles/Basal Bodies in Cells

RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner

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