Karyopherins in cancer

Çağatay, Tolga; Chook, Yuh Min

doi:10.1016/j.ceb.2018.01.006

Cited by 98 publications

(91 citation statements)

References 131 publications

(149 reference statements)

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“…In HeLa cells, cyclin‐dependent kinase inhibition blocked interphase NPC assembly leading to a reduction in NPC density, yet nuclear growth was unaffected , and ELYS depletion did not significantly affect nuclear lamin localization or import capacity . These results might be explained by an upregulation of nuclear import that is frequently observed in cancer cells . These studies highlight the importance of cell type and disease state when considering mechanisms of nuclear size control.…”

Section: Discussionmentioning

confidence: 81%

“…Changes in nuclear size are commonly used in cancer diagnosis and prognosis, yet it is unknown whether altered nuclear size contributes to, or is simply a consequence of, the pathology. Levels of nuclear transport factors are frequently altered in cancer and have begun to be targeted for cancer treatments [10,109,110,[112][113][114][115]. Our results suggest that it may also be important to examine changes in NPC densities in cancer.…”

Section: Discussionmentioning

confidence: 95%

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The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

et al. 2019

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How intracellular organelles acquire their characteristic sizes is a fundamental question in cell biology. Given stereotypical changes in nuclear size in cancer, it is important to understand the mechanisms that control nuclear size in human cells. Using a high‐throughput imaging RNAi screen, we identify and mechanistically characterize ELYS, a nucleoporin required for post‐mitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. ELYS knockdown results in small nuclei, reduced nuclear lamin B2 localization, lower NPC density, and decreased nuclear import. Increasing nuclear import by importin α overexpression rescues nuclear size and lamin B2 import, while inhibiting importin α/β‐mediated nuclear import decreases nuclear size. Conversely, ELYS overexpression increases nuclear size, enriches nuclear lamin B2 at the nuclear periphery, and elevates NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. Thus, we identify ELYS as a novel positive effector of mammalian nuclear size and propose that nuclear size is sensitive to NPC density and nuclear import capacity.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 95%

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

et al. 2019

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“…The human genome codes for approximately 20 different karyopherins [22] . While some of these receptors can mediate bidirectional transport of cargos in and out of the nucleus, most of them function exclusively as either import receptors (importins) or export receptors (exportins), such as XPO1.…”

Section: An Overview Of Nucleocytoplasmic Transport Of Proteinsmentioning

confidence: 99%

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Sendino¹,

Omaetxebarria²,

Rodríguez³

2018

CDR

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Cellular homeostasis crucially relies on the correct nucleocytoplasmic distribution of a vast number of proteins and RNA molecules, which are shuttled in and out of the nucleus by specialized transport receptors. The nuclear export receptor XPO1, also called CRM1, mediates the translocation of hundreds of proteins and several classes of RNA to the cytoplasm, and thus regulates critical signaling pathways and cellular functions. The normal function of XPO1 appears to be often disrupted in malignant cells due to gene mutations or, most commonly, aberrant overexpression. Due to its important physiological roles and its frequent alteration in human tumors, XPO1 is a promising target for cancer therapy. XPO1 inhibitors have undergone extensive testing as therapeutic agents in preclinical models of cancer, with promising results. One of these inhibitors, Selinexor, is currently being evaluated in multiple clinical trials of different types of solid tumors and hematological malignancies. Here, we review several key aspects of XPO1 function, as well as the mechanisms that may lead to its alteration in cancer, and provide an update on the status of XPO1 inhibitors being developed as drugs for cancer therapy, including the definitive results of the first clinical trials with Selinexor that have been recently published. Figure 1. Receptor-mediated nucleocytoplasmic transport of proteins. A: Illustrative overview of the nuclear import of a cargo protein bearing a "classical" NLS mediated by the Importina/Importinb heterodimer (left) and the nuclear export of a cargo protein bearing a "leucine-rich" NES mediated by XPO1 (right); B: schematic depiction of the nuclear pore complex, illustrating its main structural features; C: examples of nucleocytoplasmic transport signals. The NLSs of SV40 large T antigen (monopartite) and nucleoplasmin (bipartite) are shown, with the basic residues that characterize "classical" NLSs highlighted in red. Below, the NES of PKI and a general consensus sequence of "leucine-rich" NESs are shown. The characteristic hydrophobic residues (represented by f in the consensus) are highlighted in colors and underlined. NLS: nuclear localization signal; NES: nuclear export signal Conception of the work, draft and revision of the work: Sendino M, Omaetxebarria MJ, Rodríguez JA

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“…This reporter system consists of a fused double-GFP with an NES (2GFP-NES) and a double RFP containing an NLS (2RFP-NLS; Mertens et al, 2015). NES and NLS are conserved signal sequences that are recognized by nuclear transport receptors of exportins and importins, respectively (Christie et al, 2016;Cagatay and Chook, 2018). Thus, both protein export and import can be analyzed with this dual reporter in single cells.…”

Section: Protein Nucleocytoplasmic Transport Measurementmentioning

confidence: 99%

Differential Influence of Sample Sex and Neuronal Maturation on mRNA and Protein Transport in Induced Human Neurons

Ding

Akter

Zhang

2020

Front. Mol. Neurosci.

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Nucleocytoplasmic transport (NCT) across the nuclear envelope (NE) is tightly regulated in eukaryotic cells and is critical for maintaining cellular homeostasis. Its dysregulation leads to aging and neurodegeneration. Because they maintain aging-associated hallmarks, directly reprogrammed neurons from human fibroblasts are invaluable in understanding NCT. However, it is not clear whether NCT activity is influenced by neuronal maturation and sample sex [a key biological variable emphasized by the National Institutes of Health (NIH) policy]. We examined here NCT activity at the single-cell level by measuring mRNA subcellular distribution and protein transport in directly induced motor neurons (diMNs) from adult human fibroblasts. The results show that mRNA subcellular distribution but not protein transport is affected by neuronal maturation stages, whereas both transport processes are not influenced by the sample sex. This study also provides quantitative methods and optimized conditions for measuring NCTs of mRNAs or protein cargoes, establishing a robust way for future functional examinations of NCT activity in directly induced neurons from diseased human patients.

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Karyopherins in cancer

Cited by 98 publications

References 131 publications

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

The nucleoporin ELYS regulates nuclear size by controlling NPC number and nuclear import capacity

Hitting a moving target: inhibition of the nuclear export receptor XPO1/CRM1 as a therapeutic approach in cancer

Differential Influence of Sample Sex and Neuronal Maturation on mRNA and Protein Transport in Induced Human Neurons

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