Ran control of mitosis in human cells: gradients and local signals

Roscioli, Emanuele; Bolognesi, Alessio; Guarguaglini, Giulia; Lavia, Patrizia

doi:10.1042/bst0381709

Cited by 12 publications

(10 citation statements)

References 48 publications

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“…TPX2 gene is localized on chromosomal band 20q11, a region of frequent amplification with a strong correlation between copy number and protein expression levels [44], [45]. In addition, the important contribution of RAN to the mitotic process has also been well described [46]. Here, we report that TPX2 expression, like RAN, correlates positively with tumor grade, and was associated with poor patient survival and with a short recurrence time in HG serous EOC (Figures 2–4).…”

Section: Discussionsupporting

confidence: 58%

RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

et al. 2014

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PurposeEpithelial ovarian cancer has the highest mortality rate of all gynecological malignancies. We have shown that high RAN expression strongly correlates with high-grade and poor patient survival in epithelial ovarian cancer. However, as RAN is a small GTPase involved in two main biological functions, nucleo-cytoplasmic transport and mitosis, it is still unknown which of these functions associate with poor prognosis.MethodsTo examine the biomarker value of RAN network components in serous epithelial ovarian cancer, protein expression of six specific RAN partners was analyzed by immunohistochemistry using a tissue microarray representing 143 patients associated with clinical parameters. The RAN GDP/GTP cycle was evaluated by the expression of RANBP1 and RCC1, the mitotic function by TPX2 and IMPβ, and the nucleo-cytoplasmic trafficking function by XPO7, XPOT and IMPβ.ResultsBased on Kaplan-Meier analyses, RAN, cytoplasmic XPO7 and TPX2 were significantly associated with poor overall patient survival, and RAN and TPX2 were associated with lower disease free survival in patients with high-grade serous carcinoma. Cox regression analysis revealed that RAN and TPX2 expression were independent prognostic factors for both overall and disease free survival, and that cytoplasmic XPO7 expression was a prognostic factor for overall patient survival.ConclusionsIn this systematic study, we show that RAN and two protein partners involved in its nucleo-cytoplasmic and mitotic functions (XPO7 and TPX2, respectively) can be used as biomarkers to stratify patients based on prognosis. In particular, we reported for the first time the clinical relevance of the exportin XPO7 and showed that TPX2 expression had the strongest prognostic value. These findings suggest that protein partners in each of RAN’s functions can discriminate between different outcomes in high-grade serous epithelial ovarian cancer patients. Furthermore, these proteins point to cellular processes that may ultimately be targeted to improve the survival in serous epithelial ovarian cancer.

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Section: Discussionsupporting

confidence: 58%

RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

et al. 2014

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“…Excellent reviews of a number of seminal in vivo studies on the karyopherin/Ran dueling regulators by the Lavia group and others include [64,104]. Recently, Hasegawa et al [105] found a steep RanGTP gradient exists around the mitotic chromosomes of rapidly growing cells, while reduced RanGTP gradients are observed around the chromosomes in primary cells (HFF-1 cells).…”

Section: In Vivo Evidencementioning

confidence: 99%

Nuclear transport factors: global regulation of mitosis

Forbes

Travesa

Nord

et al. 2015

Current Opinion in Cell Biology

110

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The unexpected repurposing of nuclear transport proteins from their function in interphase to an equally vital and very different set of functions in mitosis was very surprising. The multi-talented cast when first revealed included the import receptors, importin alpha and beta, the small regulatory GTPase RanGTP, and a subset of nuclear pore proteins. In this review, we report that recent years have revealed new discoveries in each area of this expanding story in vertebrates: (a) The cast of nuclear transport receptors playing a role in mitotic spindle regulation has expanded: both transportin, a nuclear import receptor, and Crm1/Xpo1, an export receptor, are involved in different aspects of spindle assembly. Importin beta and transportin also regulate nuclear envelope and pore assembly. (b) The role of nucleoporins has grown to include recruiting the key microtubule nucleator the γ-TuRC complex and the exportin Crm1 to the mitotic kinetochores of humans. Together they nucleate microtubule formation from the kinetochores towards the centrosomes. (c) New research finds that the original importin beta/RanGTP team have been further co-opted by evolution to help regulate other cellular and organismal activities, ranging from the actual positioning of the spindle within the cell perimeter, to regulation of a newly discovered spindle microtubule branching activity, to regulation of the interaction of microtubule structures with specific actin structures. (d) Lastly, because of the multitudinous roles of karyopherins throughout the cell cycle, a recent large push toward testing their potential as chemotherapeutic targets has begun to yield burgeoning progress in the clinic.

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“…Moreover, CRM1 has additional effects on the definition of kinetochore fibers and in chromosome segregation during mitosis. In particular, CRM1 activity in metaphase and later anaphase changes repartitioning of RanGTP and consequently also of effectors on kinetochores and centrosomes [ 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

Section: The Nucleocytoplasmic Transport Machinerymentioning

confidence: 99%

Structural Basis of Targeting the Exportin CRM1 in Cancer

Dickmanns

Monecke

Ficner

2015

Cells

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Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the nucleus or the other way round, respectively. The exportin CRM1 (Chromosome region maintenance 1) exports a plethora of different protein cargoes and ribonucleoprotein complexes. Structural and biochemical analyses have enabled the deduction of individual steps of the CRM1 transport cycle. In addition, CRM1 turned out to be a valid target for anticancer drugs as it exports numerous proto-oncoproteins and tumor suppressors. Clearly, detailed understanding of the flexibility, regulatory features and cooperative binding properties of CRM1 for Ran and cargo is a prerequisite for the design of highly effective drugs. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Clinical studies revealed serious side effects of LMB, leading to a search for alternative natural and synthetic drugs and hence a multitude of novel therapeutics. The present review examines recent progress in understanding the binding mode of natural and synthetic compounds and their inhibitory effects.

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Ran control of mitosis in human cells: gradients and local signals

Cited by 12 publications

References 48 publications

RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

RAN Nucleo-Cytoplasmic Transport and Mitotic Spindle Assembly Partners XPO7 and TPX2 Are New Prognostic Biomarkers in Serous Epithelial Ovarian Cancer

Nuclear transport factors: global regulation of mitosis

Structural Basis of Targeting the Exportin CRM1 in Cancer

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