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Mammalian RanBP1 regulates centrosome cohesion during mitosis. (Articolo in rivista)

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Mammalian RanBP1 regulates centrosome cohesion during mitosis. (Articolo in rivista) (literal)

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Di Fiore B, Ciciarello M, Mangiacasale R, Palena A, Tassin AM, Cundari E, Lavia P. (2003)
Mammalian RanBP1 regulates centrosome cohesion during mitosis.
in Journal of cell science
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Di Fiore B, Ciciarello M, Mangiacasale R, Palena A, Tassin AM, Cundari E, Lavia P. (literal)

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the paper had an Editorail Highlight on that issue. The novelty of the paper is that the results help to understand the genesis of genomic instability in those cancer types that express abnormally high levels of the RanBP1 protein. This expands our understanding of genes and regulatory networks in control of cell division and may open up interesting perspectives in gene therapy of certain cancer types. The work is published in a leading international journal in cell biology with an impact factor of 7 in 2002. (literal)

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In this paper we have depicted a novel function of the Ran GTPase signalling network in mitotic control in mammalian cells. We have concentrated on RanBP1 (Ran-binding protein 1), the major effector of the Ran GTPase. Microarray-based profiling of cancer cells indicate that the RanBP1-encoding gene is frequently expressed at aberrant levels, especially in solid cancer. In this framework, it is important to understand the effects associated with abnormal expression of this gene. The results reported in this paper are of relevance in that they show that high levels of RanBP1 perturb the establishment of a functional bipolar mitotic spindle and give rise to multipolar mitoses that segregate uneven numbers of chromosomes in daughter cells. These findings can account for the high level of genomic instability observed in tumor cells in which the RanBP1 gene is overexpressed. More generally, they expand our understanding of genes and regulatory networks in control of cell division. (literal)

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The Ran GTPase plays a central function in control of nucleo-cytoplasmic transport in interphase. Mitotic roles of Ran have also been firmly established in Xenopus oocyte extracts. In this system, Ran-GTP, or the RCC1 exchange factor for Ran, drive spindle assembly by regulating the availability of 'aster-promoting activities'. In previous studies to assess whether the Ran network also influences mitosis in mammalian cells, we found that overexpression of Ran-binding protein 1 (RanBP1), a major effector of Ran, induces multipolar spindles. We now show that these abnormal spindles are generated through loss of cohesion in mitotic centrosomes. Specifically, RanBP1 excess induces splitting of mother and daughter centrioles at spindle poles; the resulting split centrioles can individually organize functional microtubule arrays, giving rise to functional spindle poles. RanBP1-dependent centrosome splitting is specifically induced in mitosis and requires microtubule integrity and Eg5 activity. In addition, we have identified a fraction of RanBP1 at the centrosome. These data indicate that overexpressed RanBP1 interferes with crucial factor(s) that control structural and dynamic features of centrosomes during mitosis and contribute to uncover novel mitotic functions downstream of the Ran network. (literal)

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