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  • The data presented above clearly indicate an important

    2019-12-02

    The data presented above clearly indicate an important role of eIF4E for the nucleocytoplasmic transport of the human iNOS mRNA. To analyze the sequence elements of the iNOS mRNA that are important for this eIF4E-mediated transport we performed transient transfection experiments using constructs containing the iNOS-5′-UTR cloned in front of the luciferase coding region with or without the iNOS 3′-UTR cloned behind the luciferase stop gpr44 inhibitor (see Fig. 8A). These transfection experiments clearly indicate that the 3′-UTR seems to be essential for the for transport of the human iNOS mRNA by eIF4E (Fig. 8B and C). In addition the pull down experiments (see Fig. S2) showed a direct interaction of eIF4E with the 3′-UTR sequence of the human iNOS mRNA. These observations parallel the results described for the eIF4E-dependent nucleocytoplasmic transport of the human cyclin D1 mRNA [18]. The eIF4E-sensitive element (4E-SE) identified in the 3′-UTR of the cyclin D1 mRNA by Culjkovic et al. also contains several AU-rich sequences. Therefore it is likely that at least in part the AREs (as found in the 3′-UTR of the human iNOS mRNA) determine whether a mRNA undergoes CRM1-dependent nucleocytoplasmic transport.
    Conclusions
    Funding This work was supported by Grant 1512-366261/758K and 961-386261/917K from the Innovation Foundation of the State of Rhineland-Palatinate, by the Collaborative Research Center SFB 553 (Project A7 to HK), and the DFG grant Li 1759/1-1 (to HK). This study was partly supported by the Federal Ministry of Education and Research (BMBF 01EO1003). The authors are responsible for the contents of this publication.
    Acknowledgments
    Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non–Hodgkin lymphoma, a heterogeneous group of human lymphoid neoplasms that have significantly increased in incidence in the United States during the past 3 decades , . Although high-dose, multi-agent chemotherapy induces high remission rates in previously untreated patients with MCL, relapse within a few years is common and contributes to a rather short median survival duration of 5 to 7 years , . Discovering new therapeutic agents with low toxicity and better outcomes for patients with MCL is clearly an ongoing challenge. The nonrandom chromosomal translocation t(11,14)(q13;32) characteristic of MCL leads to overexpression of cyclin D1, which is believed to be associated with oncogenesis. However, overexpression of cyclin D1 itself is not sufficient for development of MCL, which suggests that additional genetic events are necessary for oncogenesis . One such genetic event might involve the chromosomal region maintenance/exportin1/Xpo1 gene (CRM1). CRM1 was originally identified in the fission yeast in a genetic screen, and investigators determined that it was involved in the control of the chromosome structure . Of the seven nuclear export receptors in humans, CRM1 is the major one. This transporter has a particularly broad substrate range and mediates the export through nuclear pore complexes of leucine-rich nuclear export signal (NES)–bearing proteins and a minority of messenger and microRNAs , , , , . Mechanistic studies have demonstrated that many NES-containing signaling molecules depend on the CRM1 nuclear export pathway, including p53 , histone deacetylase 5 , protein kinase 1 , epidermal growth factor receptor , and others , . In fact, the majority of the tumor suppressor proteins are exported exclusively by CRM1 . Because these CRM1 cargos play key roles in the proliferation and survival of cancer cells, CRM1 could represent a new class of therapeutic targets for novel anticancer drug development , , , , . A well-known natural product CRM1-specific inhibitor, LMB, binds covalently to Cys528 of CRM1 through a Michael-type addition reaction and abrogates the interaction between CRM1 and its cargo protein , , gpr44 inhibitor . Although LMB possesses strong anti-tumor activity in vitro, phase I trials of LMB were discontinued because of its toxicity and lack of apparent efficacy in the tolerable dose range . Mutka et al. noted that LMB has off-target effects against proteins other than CRM1, and that derivitization of LMB can ameliorate many of the side effects of LMB in mice, indicating that LMB’s off-target effects contribute to toxicities. The finding that inhibition of CRM1 itself was not the cause of LMB’s toxicity is promising in terms of the development of anticancer drugs targeting CRM1.