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  • Sennoside C australia The large body of structural knowledge

    2020-01-14

    The large body of structural knowledge that is currently available for CRM1 has contributed to atomic level and mechanistic understanding of many steps in the CRM1 nuclear export cycle. However, structural analysis could still inform Sennoside C australia on several outstanding questions and guide future discoveries pertaining to CRM1-mediated nuclear export. The most glaring gap in current structural knowledge of this transport pathway concerns the lack of CRM1-nucleoporin structures. Are there different classes of CRM1-nucleoporin interactions, such as ones for docking onto the NPC and others for translocation? The mechanism of RanBP3 facilitated cargo loading in the nucleus is also unclear at this time, and structural work of complexes containing CRM1 and RanBP3 should shed light on this process. In addition to its hundreds of protein cargos, CRM1 also exports a subset of mRNAs in a Ran-dependent and LMB-sensitive fashion [20], [124], [125], [126], [127], [128], [129], [130], [131]. mRNA export by CRM1 likely requires NES-containing adaptors but it is currently not known if there is a general mRNA adaptor for CRM1 or specific adaptors for different mRNAs [132]. It is also not known if CRM1 shares binding interfaces with mRNA or other nucleic Sennoside C australia cargos. Structural analysis of CRM1-nucleic acid complexes may be possible and useful once identities of their adaptors are known. Finally, recent reports suggest that CRM1 is a relevant target for cancer and potentially inflammatory diseases, and efforts to design and develop CRM1 inhibitors for therapeutics has and should continue benefiting from the large body of structural data on the pathway [133], [134], [135], [136], [137]. Atomic understanding of the different steps of the CRM1 cycle and the different conformational states of CRM1 should guide discovery of reversible inhibitors for the NES binding groove and perhaps allosteric inhibitors that control CRM1 activity through binding at sites far from the NES groove.
    Conflict of interest
    Acknowledgements This work is funded by the National Institutes of HealthR01-GM069909 (YMC), Welch Foundation (I-1532; YMC), Leukemia and Lymphoma Society Scholar award (YMC), CPRIT (RP120352; YMC) and the UT Southwestern Endowed Scholars Program (YMC). We thank Q. Sun and S. Fu for critical comments.
    Introduction Nucleocytoplasmic trafficking of proteins and RNAs is mediated by the nuclear exporter chromosome region maintenance 1 (CRM1, also known as exportin 1 or XPO1) protein, which has over 230 identified cargos (Xu et al., 2012). The protein plays a critical role in nuclear export of growth and survival factors in eukaryotic cells, including transformed cells. Certain natural products (e.g., leptomycin B, ratjadone, anguinomycin, and goniothalamin (Hamamoto et al., 1985, Komiyama et al., 1985, Hayakawa et al., 1995, Kudo et al., 1998, Kudo et al., 1999, Daelemans et al., 2002, Kau et al., 2004, Meissner et al., 2004, Bonazzi et al., 2007, Mutka et al., 2009, Wach et al., 2010, Turner et al., 2012)) are inhibitors of CRM1. This discovery led to the development of CRM1-specific small molecules (e.g., N-azolylacrylates, KOS-2464, and CBS9106) as potentially useful, anti-cancer agents (Mutka et al., 2009, Sakakibara et al., 2011, Turner et al., 2012). These include the potent, second-generation CRM1-selective inhibitors of nuclear export (designated as SINE) class of agents that has added further promise of this targeted strategy for the elimination of malignant cells (Etchin et al., 2013a). Indeed, in vitro experimental scenarios have shown that the blockade of CRM1 transport by these inhibitors can induce cancer cell death, which is believed to occur by the forced nuclear retention of tumor-suppressors, transcriptional factors that are inactive in these cells due to aberrant CRM1 transport into the cytoplasm. Furthermore, treatment of various solid tumors and hematological malignancies with SINE compounds has been shown to block transformed cell proliferation and induce apoptosis in these cells in vivo (Mutka et al., 2009, Sakakibara et al., 2011, Turner et al., 2012). SINE compounds apparently have limited toxicity in normal human cells, which enhances the overall therapeutic index of these agents (Etchin et al., 2013b). In particular, KPT-330, with its well-established pharmacokinetic and pharmacodynamics properties, including high oral bioavailability, is a promising SINE that has recently entered into clinical trials. In this review, we present the cellular biology associated with the nuclear export of proteins/RNAs by CRM1, and outline the preclinical and potential clinical impact of the regulation of this protein function as a candidate therapeutic target in human malignancies.