Structural Basis of Targeting the Exportin CRM1 in Cancer

Dickmanns, Achim; Monecke, Thomas; Ficner, Ralf

doi:10.3390/cells4030538

Cited by 55 publications

(60 citation statements)

References 237 publications

(323 reference statements)

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“…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: 97%

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: 97%

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

et al. 2019

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“…However, the IC 50 of EWS cell lines to KPT-330 and the mutational status of TP53 in these cells showed no significant correlation (R 2 ¼ 0.27; P ¼ 0.15). p53 is an important cargo of CRM1 (45,46), but clearly for EWS, it is not a biomarker to predict response to KPT-330. This appears to be the same in other studies (18,19,(47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

et al. 2016

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Ewing sarcoma (EWS) is an aggressive bone malignancy that mainly affects children and young adults. The mechanisms by which EWS (EWSR1) fusion genes drive the disease are not fully understood. CRM1 (XPO1) traffics proteins from the nucleus, including tumor suppressors and growth factors, and is overexpressed in many cancers. A small-molecule inhibitor of CRM1, KPT-330, has shown therapeutic promise, but has yet to be investigated in the context of EWS. In this study, we demonstrate that CRM1 is also highly expressed in EWS. shRNA-mediated or pharmacologic inhibition of CRM1 in EWS cells dramatically decreased cell growth while inducing apoptosis, cell-cycle arrest, and protein expression alterations to several cancer-related factors. Interestingly, silencing of CRM1 markedly reduced EWS-FLI1 fusion protein expression at the posttranscriptional level and upregulated the expression of the well-established EWS-FLI1 target gene, insulin-like growth factor binding protein 3 (IGFBP3), which inhibits IGF-1. Accordingly, KPT-330 treatment attenuated IGF-1-induced activation of the IGF-1R/AKT pathway. Furthermore, knockdown of IGFBP3 increased cell growth and rescued the inhibitory effects on IGF-1 signaling triggered by CRM1 inhibition. Finally, treatment of EWS cells with a combination of KPT-330 and the IGF-1R inhibitor, linsitinib, synergistically decreased cell proliferation both in vitro and in vivo. Taken together, these findings provide a strong rationale for investigating the efficacy of combinatorial inhibition of CRM1 and IGF-1R for the treatment of EWS. Cancer Res; 76(9);

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“…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 [10,87,88,90,[104][105][106]. Our results suggest that it may also be important to examine changes in NPC densities in cancer.…”

Section: Discussionmentioning

confidence: 80%

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

Jevtić

Schibler

Pegoraro

et al. 2019

Preprint

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How intracellular organelles acquire their characteristic sizes is a fundamental cell biological question. Given the stereotypical changes in nuclear size in cancer, it is particularly important to understand the mechanisms that control nuclear size in human cells. Here we use a high-throughput imaging RNAi screen to identify and mechanistically characterize ELYS, a nucleoporin required for postmitotic nuclear pore complex (NPC) assembly, as a determinant of nuclear size in mammalian cells. We show that ELYS knockdown results in small nuclei, the accumulation of cytoplasmic lamin aggregates, 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 nuclear import decreases nuclear size. Conversely, ELYS overexpression leads to increased nuclear size, enrichment of nuclear lamin B2 staining at the nuclear periphery, and elevated NPC density and nuclear import. Consistent with these observations, knockdown or inhibition of exportin 1 increases nuclear size. In summary, we identify ELYS and NPC density as novel positive effectors of mammalian nuclear size and propose that nuclear size is controlled by nuclear import capacity. INTRODUCTIONA fundamental question in cell biology is how intracellular organelles acquire their characteristic sizes. Organelle size almost certainly impacts function. For instance, expansion of the endoplasmic reticulum (ER) occurs in response to the need for increased protein synthesis or folding [1-3]. Depending on cell-size and -type, Golgi and mitochondrial volumes must be sufficient to support cellular metabolic requirements [4-8]. The functional significance of nuclear size is a particularly important problem. Changes in nuclear size are used to diagnose and stage many forms of cancer [9-12], yet it is unknown if these nuclear size changes contribute to the disease pathology or result from it. Addressing this question requires a comprehensive understanding of the mechanisms that control nuclear size in normal and cancerous mammalian cells.The nuclear envelope (NE) is composed of an enclosed double lipid bilayer that is continuous with the ER on the exterior and lined on the inside by multiple proteins that constitute the nuclear lamina, most notably nuclear lamins [13]. Inserted into the NE are nuclear pore complexes (NPCs) that mediate nucleocytoplasmic transport of proteins and RNA [14][15][16][17]. The NPC is a large protein complex composed of multiple copies of ~30 different proteins termed nucleoporins (Nups), and distinct mechanisms are responsible for assembling NPCs into the NE after mitosis and for inserting NPCs into the NE during interphase [18,19]. Classical nuclear import is mediated by importin α/β karyopherins that transport cargos through the NPC and into the nucleoplasm where RanGTP induces cargo release through importin β binding. The three major nuclear lamins (lamin A/C, B1, and B2) are imported through this pat...

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Structural Basis of Targeting the Exportin CRM1 in Cancer

Cited by 55 publications

References 237 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

CRM1 Inhibition Promotes Cytotoxicity in Ewing Sarcoma Cells by Repressing EWS-FLI1–Dependent IGF-1 Signaling

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

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