A local high RanGTP concentration may therefore provide positional information for the formation of the spindle around the chromosomes. However, because RCC1, the GEF for Ran associates with the chromosomes in M-phase, the concentration of RanGTP may still be high enough in the vicinity of chromatin to dissociate complexes of importins and cargo proteins. A gradient of RanGTP in mitosis?Īs the cell enters mitosis and the nuclear envelope breaks down the nucleoplasm and the cytoplasm mix, diluting the high concentration of nuclear RanGTP. Interestingly, this situation is like a mirror image of mitosis when Ran releases proteins from inhibitory import receptors. Moreover, Yamaguchi and Newport (2003) have recently shown that in the presence of high levels of RanGTP the export receptor CRM1 inhibits rereplication by sequestering replication proteins inside the nucleus without exporting them to the cytoplasm. In addition, the Ran system has been demonstrated to be involved in other cell cycle regulated events, such as nuclear envelope assembly ( Hetzer et al., 2000 Zhang and Clarke, 2001) and kinetochore function ( Arnaoutov and Dasso, 2003). Recently, there have been some direct ( Askjaer et al., 2002 Bamba et al., 2002) and indirect evidence supporting a role for the Ran system in spindle assembly in mitosis in vivo ( Gruss et al., 2002 Moore et al., 2002 Trieselmann and Wilde, 2002 Li et al., 2003). Experiments in Xenopus egg extracts have shown that the dissociation of import receptors from their cargos by RanGTP is one of the mechanisms that renders several proteins competent to function in spindle formation ( Gruss et al., 2001 Nachury et al., 2001 Wiese et al., 2001). There is now substantial evidence indicating that these activities are important for spindle assembly as well. This governs the directionality of nucleocytoplasmic transport ( Mattaj and Englmeier, 1998 Görlich and Kutay, 1999). In the nucleus, RanGTP regulates the binding properties of the family of importin β–like nuclear transport receptors, promoting the dissociation of import receptors from their cargo proteins and participating in complex formation of export receptors with their cargos. The differential distribution of RanGTP between the nucleus and the cytoplasm is safeguarded by the integrity of the nuclear envelope. It relies primarily on the restriction of high concentrations of its GTP form to the nucleus. The function of Ran in nucleocytoplasmic transport during interphase has been extensively studied. General mechanism of Ran action during the cell cycle: a small protein with many tricks We then review our current knowledge on the downstream targets of Ran during mitosis and we focus on the multiple functions performed by the targeting protein for Xklp2 (TPX2), one central target of Ran in spindle assembly. Here, we examine some controversial data on the role of chromosomes and the Ran model in spindle assembly. A number of recent excellent reviews cover different aspects of Ran functions in spindle assembly and in other cellular processes ( Clarke and Zhang, 2001 Moore, 2001 Dasso, 2002 Hetzer et al., 2002 Quimby and Dasso, 2003 Weis, 2003 Di Fiore et al., 2004). Substantial evidence coming from several labs supports a model in which the small GTPase Ran in its GTP-bound form (RanGTP) coordinates spatially spindle assembly. This task is performed by microtubules that assemble into a spindle-shaped apparatus around the chromosomes. A central goal of cell division in eukaryotes is to separate two identical copies of the DNA and evenly distribute them to the daughter cells.
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