Mitotic Functions of the Ran GTPase Network: the Importance of Being in the Right Place at the Right Time

Fiore, Barbara; Ciciarello, Marilena; Lavia, Patrizia

doi:10.4161/cc.3.3.641

Cited by 69 publications

(62 citation statements)

References 73 publications

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“…[56][57][58][59][60][61][62] Aberrant nuclear localization of membrane receptors in cancer cells may be due to an increase in nuclear core complex activity, since nuclear core complex proteins such as Ran are often over-expressed in several types of cancer. 63,64 Consistent with this hypothesis, we noticed an over-expression of Ran protein in TOVs of all grades compared to LMPs. Ran is a small GTPbinding protein essential for the nucleocytoplasmic transport through the nuclear pore complex and is also involved in nuclear organization and cell cycle progression.…”

Section: Discussionsupporting

confidence: 77%

“…Ran is a small GTPbinding protein essential for the nucleocytoplasmic transport through the nuclear pore complex and is also involved in nuclear organization and cell cycle progression. 64 Its high expression in ovarian cancer cells also correlates with high stage disease. In addition to its capacity to distinguish between tumors of G0 and G1, Ran presented the highest combination of sensitivity and specificity for diagnosis (LMP or TOV) as well as prognosis.…”

Section: Discussionmentioning

confidence: 99%

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Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

Ouellet

Guyot

Page

et al. 2006

Intl Journal of Cancer

118

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Molecular profiling is a powerful approach to identify potential clinical markers for diagnosis and prognosis as well as providing a better understanding of the biology of epithelial ovarian cancer. On the basis of the analysis of HuFL expression data, we have previously identified genes that distinguish low malignant potential and invasive serous epithelial ovarian tumors. In this study, we used immunohistochemistry to monitor a subset of differently expressed candidates (Ahr, Paep, Madh3, Ran, Met, Mek1, Ccne1, Ccd20, Cks1 and Cas). A tissue array composed of 244 serous tumors of different grades (0–3) and stages (I–IV) was used in this analysis. All markers assayed presented differential protein expression between serous tumors of low and high grade. Significant differences in Ccne1 and Ran expression were observed in a comparison of low malignant potential and grade 1 tumor samples (p < 0.01). In addition, irrespective of the grade, Ccne1, Ran, Cdc20 and Cks1 showed significant differences of expression in association with the clinical stage of disease. While high level of Ccne1 have previously been associated with poor outcomes, here we found that high level of either Ran or Cdc20 appear to be more tightly associated with a poor prognosis (p < 0.001, 0.03, respectively). The application of these biomarkers in both the initial diagnosis and prognostic attributes of patients with epithelial ovarian tumors should prove to be useful in patient management. © 2006 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

Ouellet

Guyot

Page

et al. 2006

Intl Journal of Cancer

118

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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: 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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“…Ran and importin-b are therefore viewed as global mitotic regulators (reviewed by Ciciarello et al, 2007;Clarke and Zhang, 2008;Kalab and Heald, 2008). 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).…”

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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Mitotic Functions of the Ran GTPase Network: the Importance of Being in the Right Place at the Right Time

Abstract: The kinesin XCTK2 has recently been identified as a novel Ran-GTP dependent SAF (Ems-McClung SC, Zheng Y and Walczak CE. Importin a/b and Ran-GTP regulate XCTK2 microtubule binding through a bipartite NLS. Mol Biol Cell

Cited by 69 publications

References 73 publications

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

Tissue array analysis of expression microarray candidates identifies markers associated with tumor grade and outcome in serous epithelial ovarian cancer

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

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

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