Chromosomal gain promotes formation of a steep RanGTP gradient that drives mitosis in aneuploid cells

Hasegawa, Keisuke; Ryu, Sangwon; Kaláb, Petr

doi:10.1083/jcb.201206142

Cited by 38 publications

(59 citation statements)

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“…1D), consistent with previous results arguing that Ran-regulated, TPX2-mediated microtubule nucleation contributes to setting spindle length (27). Taken together with previous results, these data demonstrate that spindle length is not influenced by the amplitude of the RanGTP gradient (19,25) or the length scale of the RanGTP gradient, despite the importance of the Ran pathway for spindle assembly and spindle length (12,13,(18)(19)(20)(21)(22)(23). It is unclear how RanGTP could regulate microtubule nucleation (12,13,20) without the spatial organization of RanGTP influencing spindle morphology.…”

Section: Resultssupporting

confidence: 81%

“…We wondered whether the localization of SAFs by microtubules might explain why the length of the spindle is not influenced by the length of the Ran gradient (Fig. 1), even though the Ran pathway regulates microtubule nucleation and is required for proper spindle assembly (12,13,(18)(19)(20)(21)(22)(23). SAFs are known to regulate microtubule nucleation and other behaviors of microtubules (12)(13)(14).…”

Section: Resultsmentioning

confidence: 99%

“…We thus used RNAi to knock down RanGAP in human tissue culture cells and visualized the RanGTP gradient by fluorescence lifetime imaging microscopy (FLIM) measurements of the FRET biosensor (pSG8 RBP-4) (19) (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the length of the spindle is not affected when RanGTP is perturbed by modifying RCC1 expression (19) or through use of the mutant RanT24N (25), which acts to inhibit RCC1. As discussed above, mathematical models predict that the length scale of the gradient should be determined by the distance RanGTP diffuses before it is converted to RanGDP and by the hydrolysis rate of RanGTP, which depends on the concentration of RanGAP, and the diffusion coefficient of RanGTP (3).…”

Section: Significancementioning

confidence: 99%

“…RanGTP activates spindle assembly factors (SAFs) that control microtubule nucleation and other aspects of microtubule behaviors (18). Previous work demonstrated that the Ran pathway is essential for proper spindle assembly in meiosis II and mitosis (12,13,(18)(19)(20)(21)(22)(23), but the importance of the spatial organization of the Ran pathway remains unclear. Förster resonance energy transfer (FRET) biosensors have been used to show that RanGTP forms soluble gradients around chromosomes (12, 13), and because RanGTP regulates microtubule nucleation (12,13,20), it has been proposed that the Ran gradient controls the spatial distribution of microtubule nucleation (12, 13) and hence is a major determinant of spindle length (15, 16).…”

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confidence: 99%

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Spatial organization of the Ran pathway by microtubules in mitosis

Needleman

2016

Proc. Natl. Acad. Sci. U.S.A.

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Concentration gradients of soluble proteins are believed to be responsible for control of morphogenesis of subcellular systems, but the mechanisms that generate the spatial organization of these subcellular gradients remain poorly understood. Here, we use a newly developed multipoint fluorescence fluctuation spectroscopy technique to study the ras-related nuclear protein (Ran) pathway, which forms soluble gradients around chromosomes in mitosis and is thought to spatially regulate microtubule behaviors during spindle assembly. We found that the distribution of components of the Ran pathway that influence microtubule behaviors is determined by their interactions with microtubules, resulting in microtubule nucleators being localized by the microtubules whose formation they stimulate. Modeling and perturbation experiments show that this feedback makes the length of the spindle insensitive to the length scale of the Ran gradient, allows the spindle to assemble outside the peak of the Ran gradient, and explains the scaling of the spindle with cell size. Such feedback between soluble signaling pathways and the mechanics of the cytoskeleton may be a general feature of subcellular organization.RanGTP gradient | spatial organization | microtubule nucleation | feedback loop | spindle size C ells exhibit internal order over a range of length scales (1). The manners in which nanometer-sized proteins specify micrometer-scale subcellular organization remain poorly understood. Either mechanics or chemistry could in principle produce order at length scales of cellular dimensions. The simplest mechanical phenomena result from the cytoskeleton: Filaments can be microns long and thus their individual lengths may even be sufficient to specify large-scale subcellular organization. Chemical processes can produce large, defined length scales through the interplay between diffusion and reactions (2). The simplest reaction-diffusion phenomenon, which has been widely discussed in the context of subcellular organization, is a scenario in which a signaling molecule is phosphorylated at one location in a cell and diffuses away and gradually dephosphorylates (3). Simple mathematical models of such source-sink scenarios predict that the resulting steady-state profile will be an exponentially decreasing gradient of the phosphorylated form around the source, with a length scale of λ = ffiffiffiffiffiffiffiffi ffi D=k p , where D is the diffusion coefficient of the signaling molecule and k is the rate of dephosphorylation (3). λ is the average distance a molecule diffuses before it is dephosphorylated.Although mechanics and chemistry are individually sufficient to give rise to structure at micrometer-length scales, increasing evidence suggests that the joint contribution of both of them leads to novel phenomena that might be important for subcellular organization: The interactions of diffusible molecules with the cytoskeleton can alter their mobility and localization, greatly modifying reaction-diffusion processes (4-8); large-scale patterns can...

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Section: Resultssupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Spatial organization of the Ran pathway by microtubules in mitosis

Needleman

2016

Proc. Natl. Acad. Sci. U.S.A.

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Nucleosome functions in spindle assembly and nuclear envelope formation

Zierhut

2015

BioEssays

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Summary Chromosomes are not only carriers of the genetic material, but also actively regulate the assembly of complex intracellular architectures. During mitosis, chromosome-induced microtubule polymerisation ensures spindle assembly in cells without centrosomes and plays a supportive role in centrosome-containing cells. Chromosomal signals also mediate post-mitotic nuclear envelope (NE) re-formation. Recent studies using novel approaches to manipulate histones in oocytes, where functions can be analysed in the absence of transcription, have established that nucleosomes, but not DNA alone, mediate the chromosomal regulation of spindle assembly and NE formation. Both processes require the generation of RanGTP by RCC1 recruited to nucleosomes but nucleosomes also acquire cell cycle stage specific regulators, Aurora B in mitosis and ELYS, the initiator of nuclear pore complex assembly, at mitotic exit. Here, we review the mechanisms by which nucleosomes control assembly and functions of the spindle and the NE, and discuss their implications for genome maintenance.

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Numerical analysis of electromagnetic interactions by a cell during the mitosis phases

Mangini

Muzi

Frezza

2018

Numer Methods Biomed Eng

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In this work, a numerical study of the interaction of an electromagnetic field with a biological cell in the different phases of mitosis is presented. In particular, the validity of the single-shell model during mitosis from a geometrical viewpoint has been considered. We consider the Jurkat cell for our analysis and model the content of the cell, composed by the nucleus and different organelles immersed in cytoplasm and delimited by the cell membrane, as a single material with appropriate electromagnetic properties derived by making use of effective medium approximation methods, i.e., we used a quasistatic approach to deal with the cell. To validate the model, a comparison between the original and 2 approximated geometry models is made and the results are in very good accordance. Subsequently, an analysis of the scattered field indicates that the most sensitive component to the mitosis phase is the one parallel to the segment joining the centers of the cells.

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Chromosomal gain promotes formation of a steep RanGTP gradient that drives mitosis in aneuploid cells

Abstract: The chromosome-centered RanGTP gradient, which is strongly reduced in slow-growing normal cells, is amplified by chromosomal gain and is required for mitosis in rapidly growing aneuploid cells.

Cited by 38 publications

References 39 publications

Spatial organization of the Ran pathway by microtubules in mitosis

Spatial organization of the Ran pathway by microtubules in mitosis

Nucleosome functions in spindle assembly and nuclear envelope formation

Numerical analysis of electromagnetic interactions by a cell during the mitosis phases

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