Cancer and the Nuclear Pore Complex

Simon, Dan N.; Rout, Michael P.

doi:10.1007/978-1-4899-8032-8_13

Cited by 106 publications

(103 citation statements)

References 161 publications

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“…Larger macromolecules can bypass the selectivity barrier of the NPC by interacting with TFs that shuttle cargo through the central channel of the pore. In pathological conditions, including many cancers and viral infections, the NPC is hijacked and used to transport undesired particles, or it is modified to attenuate the cellular responses to disease onset (5,6).…”

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confidence: 99%

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Raveh

Karp

Sparks

et al. 2016

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

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131

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Nucleocytoplasmic transport is mediated by the interaction of transport factors (TFs) with disordered phenylalanine-glycine (FG) repeats that fill the central channel of the nuclear pore complex (NPC). However, the mechanism by which TFs rapidly diffuse through multiple FG repeats without compromising NPC selectivity is not yet fully understood. In this study, we build on our recent NMR investigations showing that FG repeats are highly dynamic, flexible, and rapidly exchanging among TF interaction sites. We use unbiased long timescale all-atom simulations on the Anton supercomputer, combined with extensive enhanced sampling simulations and NMR experiments, to characterize the thermodynamic and kinetic properties of FG repeats and their interaction with a model transport factor. Both the simulations and experimental data indicate that FG repeats are highly dynamic random coils, lack intrachain interactions, and exhibit significant entropically driven resistance to spatial confinement. We show that the FG motifs reversibly slide in and out of multiple TF interaction sites, transitioning rapidly between a strongly interacting state and a weakly interacting state, rather than undergoing a much slower transition between strongly interacting and completely noninteracting (unbound) states. In the weakly interacting state, FG motifs can be more easily displaced by other competing FG motifs, providing a simple mechanism for rapid exchange of TF/FG motif contacts during transport. This slide-and-exchange mechanism highlights the direct role of the disorder within FG repeats in nucleocytoplasmic transport, and resolves the apparent conflict between the selectivity and speed of transport.nuclear pore | molecular dynamics | nucleoporins | transport factors | NMR T he nuclear pore complex (NPC) regulates macromolecular transport between the nucleus and the cytoplasm in all eukaryotic cells (1, 2). The NPC allows for passive diffusion of small molecules including sugars, ions, and water, while simultaneously imposing size-dependent exclusion of macromolecules without nuclear transport factor (TF) binding sites, generating unique nuclear and cytoplasmic compartments (3, 4). Larger macromolecules can bypass the selectivity barrier of the NPC by interacting with TFs that shuttle cargo through the central channel of the pore. In pathological conditions, including many cancers and viral infections, the NPC is hijacked and used to transport undesired particles, or it is modified to attenuate the cellular responses to disease onset (5, 6).TFs traverse the NPC by selective and reversible association with disordered phenylalanine-glycine (FG) repeat domains of the FG nucleoporin proteins (FG Nups), which line the surface of the NPC (7-14). Each FG repeat domain consists of 5-50 FG repeats. In turn, each FG repeat consists of a single FG motif of various sequence flavors, such as the FSFG and GLFG motifs, and 10-30 spacer residues that separate consecutive FG motifs (15, 16). The spacer residues are strongly hydrophilic (17) and rich ...

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confidence: 99%

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Raveh

Karp

Sparks

et al. 2016

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

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131

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“…Understanding how Nup98 regulates expression of target genes remains an extremely relevant question, as many patients suffering from acute myeloid leukemia (AML) harbor mutations in which the N terminus of Nup98 is translocated with the C terminus of one of ∼30 different translocation partners (Xu and Powers 2009;Gough et al 2011;Franks and Hetzer 2013;Simon and Rout 2014). The mechanism of Nup98 translocation-mediated leukemias is poorly understood.…”

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confidence: 99%

Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells

et al. 2017

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Recent studies have shown that a subset of nucleoporins (Nups) can detach from the nuclear pore complex and move into the nuclear interior to regulate transcription. One such dynamic Nup, called Nup98, has been implicated in gene activation in healthy cells and has been shown to drive leukemogenesis when mutated in patients with acute myeloid leukemia (AML). Here we show that in hematopoietic cells, Nup98 binds predominantly to transcription start sites to recruit the Wdr82–Set1A/COMPASS (complex of proteins associated with Set1) complex, which is required for deposition of the histone 3 Lys4 trimethyl (H3K4me3)-activating mark. Depletion of Nup98 or Wdr82 abolishes Set1A recruitment to chromatin and subsequently ablates H3K4me3 at adjacent promoters. Furthermore, expression of a Nup98 fusion protein implicated in aggressive AML causes mislocalization of H3K4me3 at abnormal regions and up-regulation of associated genes. Our findings establish a function of Nup98 in hematopoietic gene activation and provide mechanistic insight into which Nup98 leukemic fusion proteins promote AML.

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“…Mutations of exportin-5 (XPO5) and exportin-1 (XPO1)/CRM1, members of export receptors (8)(9)(10), are found in solid cancer and leukemia, respectively. Four nucleoporins-Nup98, Nup214/CAN, Nup358/ RanBP2, and Tpr-have been reported to form chimeric proteins by chromosomal translocations mainly in leukemia (11)(12)(13)(14)(15). Nup214, located at the cytoplasmic filament of the NPC, interacts with NTRs to control macromolecular transport.…”

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confidence: 99%

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

Saito

Cigdem

Okuwaki

et al. 2016

Molecular and Cellular Biology

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c Nuclear-cytoplasmic transport through nuclear pore complexes is mediated by nuclear transport receptors. Previous reports have suggested that aberrant nuclear-cytoplasmic transport due to mutations or overexpression of nuclear pore complexes and nuclear transport receptors is closely linked to diseases. Nup214, a component of nuclear pore complexes, has been found as chimeric fusion proteins in leukemia. Among various Nup214 fusion proteins, SET-Nup214 and DEKNup214 have been shown to be engaged in tumorigenesis, but their oncogenic mechanisms remain unclear. In this study, we examined the functions of the Nup214 fusion proteins by focusing on their effects on nuclear-cytoplasmic transport. We found that SET-Nup214 and DEK-Nup214 interact with exportin-1 (XPO1)/CRM1 and nuclear RNA export factor 1 (NXF1)/TAP, which mediate leucine-rich nuclear export signal (NES)-dependent protein export and mRNA export, respectively. SET-Nup214 and DEK-Nup214 decreased the XPO1-mediated nuclear export of NES proteins such as cyclin B and proteins involved in the NF-B signaling pathway by tethering XPO1 onto nuclear dots where Nup214 fusion proteins are localized. We also demonstrated that SET-Nup214 and DEK-Nup214 expression inhibited NF-B-mediated transcription by abnormal tethering of the complex containing p65 and its inhibitor, IB, in the nucleus. These results suggest that SETNup214 and DEK-Nup214 perturb the regulation of gene expression through alteration of the nuclear-cytoplasmic transport system. Biological macromolecules are transported between the nucleus and the cytoplasm in response to extracellular signals. Transport of molecules with a molecular mass greater than 40 kDa does not occur by simple diffusion but is generally facilitated by nuclear transport receptors (NTRs) through nuclear pore complexes (NPCs) embedded in the nuclear envelope (1-3). Controlled nuclear-cytoplasmic transport plays important roles in maintaining cellular integrity in eukaryotic cells. It is reported that aberrant subcellular localization of some proteins is associated with various cancer cases (4). p53 has nuclear localization signals (NLSs) and nuclear export signals (NESs), and the accumulation of p53 in the cytoplasm has been reported to be a prognostic indicator in cancer (5). The nuclear factor B (NF-B) transcription factor is observed mainly in the cytoplasm in normal cells, whereas in many cancer cells, it is localized largely in the nucleus (6).In addition to aberrant subcellular localization of proteins in cancer, mutations of genes encoding NTRs and NPC components are found in various types of cancer (7). Mutations of exportin-5 (XPO5) and exportin-1 (XPO1)/CRM1, members of export receptors (8-10), are found in solid cancer and leukemia, respectively. Four nucleoporins-Nup98, Nup214/CAN, Nup358/ RanBP2, and Tpr-have been reported to form chimeric proteins by chromosomal translocations mainly in leukemia (11-15). Nup214, located at the cytoplasmic filament of the NPC, interacts with NTRs to control macromolecular transport....

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Cancer and the Nuclear Pore Complex

Cited by 106 publications

References 161 publications

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Slide-and-exchange mechanism for rapid and selective transport through the nuclear pore complex

Nup98 recruits the Wdr82–Set1A/COMPASS complex to promoters to regulate H3K4 trimethylation in hematopoietic progenitor cells

Leukemia-Associated Nup214 Fusion Proteins Disturb the XPO1-Mediated Nuclear-Cytoplasmic Transport Pathway and Thereby the NF-κB Signaling Pathway

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