Spatial and temporal coordination of mitosis by Ran GTPase

Clarke, Paul R.; Zhang, Chuanmao

doi:10.1038/nrm2410

Cited by 394 publications

(452 citation statements)

References 162 publications

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“…During early mitosis, Ran is dispersed in the cytoplasm during chromatin condensation into chromosomes and the NE disassembly, while RCC1 stays bound to the chromosomes. In the Ran-GTP gradient theory [23], high concentrations of Ran-GTP around the RCC1-bound chromosomes in metaphase should prevent the binding of importin-β with importin-α by preferentially binding with importin-β, resulting in the combination of importin-α with the spindle assembly factors such as the NLS proteins TPX2 and NuMA. In experimental conditions for spindle assembly in M phase egg extracts, RanQ69L-GTP dissociates NLS proteins from endogenous importin-α or directly affects importin-β by preferentially interacting with importin-β and lifting its inhibitory effects on these proteins for spindle assembly [42,43].…”

Section: Discussionmentioning

confidence: 99%

Chromatin-bound NLS proteins recruit membrane vesicles and nucleoporins for nuclear envelope assembly via importin-α/β

Liu

et al. 2012

Cell Res

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The mechanism for nuclear envelope (NE) assembly is not fully understood. Importin-β and the small GTPase Ran have been implicated in the spatial regulation of NE assembly process. Here we report that chromatin-bound NLS (nuclear localization sequence) proteins provide docking sites for the NE precursor membrane vesicles and nucleoporins via importin-α and -β during NE assembly in Xenopus egg extracts. We show that along with the fast recruitment of the abundant NLS proteins such as nucleoplasmin and histones to the demembranated sperm chromatin in the extracts, importin-α binds the chromatin NLS proteins rapidly. Meanwhile, importin-β binds cytoplasmic NE precursor membrane vesicles and nucleoporins. Through interacting with importin-α on the chromatin NLS proteins, importin-β targets the membrane vesicles and nucleoporins to the chromatin surface. Once encountering Ran-GTP on the chromatin generated by RCC1, importin-β preferentially binds Ran-GTP and releases the membrane vesicles and nucleoporins for NE assembly. NE assembly is disrupted by blocking the interaction between importin-α and NLS proteins with excess soluble NLS proteins or by depletion of importin-β from the extract. Our findings reveal a novel molecular mechanism for NE assembly in Xenopus egg extracts.

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Section: Discussionmentioning

confidence: 99%

Chromatin-bound NLS proteins recruit membrane vesicles and nucleoporins for nuclear envelope assembly via importin-α/β

Liu

et al. 2012

Cell Res

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“…Therefore, even when attached to the surface of nanoparticles, RanGTP is able to recruit importin. This step is essential for signal transduction, leading to the release in the cytoplasm of the MAPs that enhance microtubule nucleation and stabilization 26 (Fig. 1b).…”

Section: Magnetic Nanoparticles Controlling Microtubule Assemblymentioning

confidence: 99%

“…1b) 24,26 . The RCC1-NP signalling pathway involves the cycling of RanGTP by RCC1-NPs, and therefore contains an additional biochemical step in which Ran reactivity is tightly coupled to its diffusion within the cytoplasm (Fig.…”

Section: Reaction-diffusion Influences Microtubule Assemblymentioning

confidence: 99%

“…Interestingly, the reaction cycles of these proteins are tightly coupled to their diffusion 21 . More specifically, we investigate the Ran/RCC1 signalling network, which regulates microtubule self-assembly during mitosis [22][23][24][25][26] . To spatially control microtubule assembly, we first conjugate superparamagnetic nanoparticles to RanGTP (Ran-NPs) and RCC1 (RCC1-NPs) proteins and demonstrate the efficiency of the magnetic modulation of signalling pathways in cell extracts.…”

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Spatiotemporal control of microtubule nucleation and assembly using magnetic nanoparticles

et al. 2013

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Decisions on the fate of cells and their functions are dictated by the spatiotemporal dynamics of molecular signalling networks. However, techniques to examine the dynamics of these intracellular processes remain limited. Here, we show that magnetic nanoparticles conjugated with key regulatory proteins can artificially control, in time and space, the Ran/RCC1 signalling pathway that regulates the cell cytoskeleton. In the presence of a magnetic field, RanGTP proteins conjugated to superparamagnetic nanoparticles can induce microtubule fibres to assemble into asymmetric arrays of polarized fibres in Xenopus laevis egg extracts. The orientation of the fibres is dictated by the direction of the magnetic force. When we locally concentrated nanoparticles conjugated with the upstream guanine nucleotide exchange factor RCC1, the assembly of microtubule fibres could be induced over a greater range of distances than RanGTP particles. The method shows how bioactive nanoparticles can be used to engineer signalling networks and spatial self-organization inside a cell environment.

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“…GTP-bound Ran activates a large set of factors in these processes, whereas the major Ran effector, importin-b, exerts an antagonistic function by engaging these factors in complexes in which they are 'shielded' from RanGTP-dependent activation. 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).…”

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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Spatial and temporal coordination of mitosis by Ran GTPase

Cited by 394 publications

References 162 publications

Chromatin-bound NLS proteins recruit membrane vesicles and nucleoporins for nuclear envelope assembly via importin-α/β

Chromatin-bound NLS proteins recruit membrane vesicles and nucleoporins for nuclear envelope assembly via importin-α/β

Spatiotemporal control of microtubule nucleation and assembly using magnetic nanoparticles

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

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