Involvement of CRM1, a nuclear export receptor, in mRNA export in mammalian cells and fission yeast

Watanabe, Mina; Fukuda, Makoto; Yoshida, Minoru; Yanagida, Mitsuhiro; Nishida, Eisuke

doi:10.1046/j.1365-2443.1999.00259.x

Cited by 41 publications

(36 citation statements)

References 29 publications

(50 reference statements)

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“…However, there has been little information on the effects of these drugs on the expression of exportins, which might be correlated to their growth inhibitory activity. Therefore, in the present study, we examined the effects of DVD on expression of XPO1 (14,17) and XPOt (8) which play essential roles in the transport namics Tokyo Ltd., Tokyo, Japan) as described previously (9,11,15). The results indicated that the gene expression of XPO1 was reduced time-dependently by 20% and that of XPOt by 40% after 72 h of the DVD treatment (Fig.…”

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confidence: 66%

1,25-Dihydroxyvitamin D3 suppresses exportin expression in human promyelocytic leukemia HL-60 cells

et al. 2006

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The active form of vitamin D 3 , 1α,25-dihydroxyvitamin D 3 (DVD), is a potent inducer of cell differentiation and inhibits proliferation of cells such as human promyelocytic leukemia HL-60 cells.In the present study, we examined the effects of DVD on the expression of exportin-1 and exportin-t, which play essential roles in the transport of mRNA and tRNA, respectively. The results of reverse transcription-polymerase chain reaction and quantitative real-time polymerase chain reaction indicated that DVD down-regulated the gene expression of these exportins. Western blotting revealed the decreased production of these proteins in DVD-treated cells. Thus, the present findings of decreased expression of exportin-1 and exportin-t induced by DVD can be correlated to inhibition of the proliferation of HL-60 cells.The physiologically active vitamin D 3 metabolite, 1α,25-dihydroxyvitamin D 3 (DVD), not only contributes to calcium homeostasis but also regulates cell proliferation and differentiation (4,10,13,16). It is a potent inducer of the differentiation of human promyelocytic leukemia HL-60 cells into the monocyte/macrophage lineage (4, 10, 16). In our previous study, we demonstrated that DVD suppressed the gene expression of eukaryotic translation initiation factor 2 (eIF-2) in these cells (15). Since eIF-2 is one of the key initiation factors controlling translation for the synthesis of new proteins, the down-regulated expression could be correlated to growth inhibition of these cells by DVD.It is known that nuclear transport factors play important roles in cellular proliferation and differentiation (6). These shuttling factors include importins and exportins. Importins play pivotal roles in transport into the nucleus of specific substrates such as NF-kappaB, ribosomal protein L12, and the signal recognition particle protein (3,5,6,12). On the other hand, nuclear export of specific macromolecules is mediated by exportins. RNAs are synthesized in the nucleus and after several steps in the maturation process are exported to the cytoplasm. Exportin-1 (XPO1), also called CRM1, is essential for the transport of mRNA (14) and exportin-t (XPOt) is a specific mediator of the export of tRNA (8).Previously it was shown that 12-O-tetradecanoylphorbol-13-acetate-induced differentiation of HL-60 cells resulted in the down-regulation of importin α1 and α4 expression (6). Since DVD is similar to the phorbol ester in that it can lead these cells toward a macrophage phenotype (10), DVD is expected to down-regulate the expression of importins. However, there has been little information on the effects of these drugs on the expression of exportins, which might be correlated to their growth inhibitory activity. Therefore, in the present study, we examined the effects of DVD on expression of XPO1 (14, 17) and XPOt (8) which play essential roles in the transport

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1,25-Dihydroxyvitamin D3 suppresses exportin expression in human promyelocytic leukemia HL-60 cells

et al. 2006

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“…To examine whether eIF4G, eIF4E, and the eIF4E kinase, Mnk1, actively shuttle between the nucleus and the cytoplasm using this pathway, we treated cells with LMB, an inhibitor of CRM1-/exportin 1-mediated nuclear export (28,55). NIH 3T3 cells were transfected with vectors containing either FLAG-tagged eIF4GI (46) or a myctagged version of Mnk1 (56). After 48 h, cells were treated with LMB for 3 h and the endogenous eIF4E and eIF4GI or transfected FLAG-eIF4GI or myc-Mnk1 was localized using the appropriate antibody (Fig.…”

Section: Vol 21 2001 Eif4g Interacts With Cbc In the Nucleus 3635mentioning

confidence: 99%

Interaction of Eukaryotic Translation Initiation Factor 4G with the Nuclear Cap-Binding Complex Provides a Link between Nuclear and Cytoplasmic Functions of the m⁷Guanosine Cap

McKendrick

Thompson

Ferreira³

et al. 2001

Molecular and Cellular Biology

104

114

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In eukaryotes the majority of mRNAs have an m 7 G cap that is added cotranscriptionally and that plays an important role in many aspects of mRNA metabolism. The nuclear cap-binding complex (CBC; consisting of CBP20 and CBP80) mediates the stimulatory functions of the cap in pre-mRNA splicing, 3 end formation, and U snRNA export. As little is known about how nuclear CBC mediates the effects of the cap in higher eukaryotes, we have characterized proteins that interact with CBC in HeLa cell nuclear extracts as potential mediators of its function. Using cross-linking and coimmunoprecipitation, we show that eukaryotic translation initiation factor 4G (eIF4G), in addition to its function in the cytoplasm, is a nuclear CBC-interacting protein. We demonstrate that eIF4G interacts with CBC in vitro and that, in addition to its cytoplasmic localization, there is a significant nuclear pool of eIF4G in mammalian cells in vivo. Immunoprecipitation experiments suggest that, in contrast to the cytoplasmic pool, much of the nuclear eIF4G is not associated with eIF4E (translation cap binding protein of eIF4F) but is associated with CBC. While eIF4G stably associates with spliceosomes in vitro and shows close association with spliceosomal snRNPs and splicing factors in vivo, depletion studies show that it does not participate directly in the splicing reaction. Taken together the data indicate that nuclear eIF4G may be recruited to pre-mRNAs via its interaction with CBC and accompanies the mRNA to the cytoplasm, facilitating the switching of CBC for eIF4F. This may provide a mechanism to couple nuclear and cytoplasmic functions of the mRNA cap structure.RNAs transcribed by RNA polymerase II (pol II) are characterized by an inverted m 7 G(5Ј)ppp(5Ј)N cap. The capping of the pre-mRNA occurs cotranscriptionally (50, 52) and is achieved by recruitment of the capping enzyme to the phosphorylated C-terminal domain of the largest subunit of pol II (5,22,36). The cap contributes to many aspects of pol II transcript metabolism, including protection against 5Ј-3Ј exonucleases, facilitating efficient pre-mRNA splicing, 3Ј end formation, U snRNA and mRNA nuclear export, and translation of mRNAs (32,34).Two distinct families of cap binding proteins (CBPs) mediate the stimulatory effects of the cap structure. In the nucleus, the cap structure interacts with the nuclear cap-binding complex (CBC), a heterodimer consisting of two highly conserved polypeptides, CBP80 and CBP20 (20,23,54). CBC plays a direct role in pre-mRNA splicing, 3Ј end formation, and U snRNA export (reviewed in reference 32). In pre-mRNA splicing CBC promotes the association of U1 snRNP with the cap-proximal 5Ј splice site (31,33). In Saccharomyces cerevisiae, CBC interacts directly with yeast-specific components of the U1 snRNP (13,15). This contrasts with the mammalian system, where there is no evidence of a direct interaction between CBC and U1 snRNP (33). Although CBC is required for efficient 3Ј end cleavage of pre-mRNA, it is not required for polyadenylation per se (11)....

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“…Studies in Scizosaccharomyces pombe identified the cellular target of LMB as the CRM1 (chromosomal region maintenance)/exportin 1 protein (11), which is critical for the export of RNA and proteins containing a nuclear export sequence (NES). In the case of RNA export, CRM1 binds to ribonuclear proteins containing the NES motif (12)(13)(14)(15). For example, the export of Rev-response element-containing human immunodeficiency virus (HIV) RNA is inhibited by LMB (13).…”

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Leptomycin B, an Inhibitor of the Nuclear Export Receptor CRM1, Inhibits COX-2 Expression

Jang¹,

Muñoz-Nájar²,

Paik³

et al. 2003

Journal of Biological Chemistry

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102

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Cyclooxygenase (COX)-2, the inducible prostaglandin synthase, is overexpressed in cancer and chronic inflammatory diseases. Post-transcriptional regulation of COX-2 mRNA is important in controlling the expression of the COX-2 gene. Here, we report that leptomycin B (LMB), a specific inhibitor of the nuclear export factor CRM1 potently inhibits the stabilization of COX-2 mRNA in MDA-MB-231 human mammary cancer cells. However, COX-2 promoter-driven reporter gene expression is not inhibited by LMB, suggesting that LMB acts at the post-transcriptional level. Subcellular fractionation experiments indicate that LMB inhibited the time-dependent export of COX-2 mRNA into the membrane-bound polysomal compartment at the endoplasmic reticulum. LMB suppressed COX-2 expression by interleukin-1␤ in HT-29 human colon cancer cells and in human umbilical vein endothelial cells but had no effect on COX-2 expression induced by Escherichia coli lipopolysaccharide in monocytic THP-1 cells. These data suggest that the nuclear export of COX-2 mRNA may be rate-liming in a cell-specific manner. LMB may be useful to control COX-2 expression in various human diseases in which COX-2 plays a pathogenetic role.

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Involvement of CRM1, a nuclear export receptor, in mRNA export in mammalian cells and fission yeast

Cited by 41 publications

References 29 publications

1,25-Dihydroxyvitamin D3 suppresses exportin expression in human promyelocytic leukemia HL-60 cells

1,25-Dihydroxyvitamin D3 suppresses exportin expression in human promyelocytic leukemia HL-60 cells

Interaction of Eukaryotic Translation Initiation Factor 4G with the Nuclear Cap-Binding Complex Provides a Link between Nuclear and Cytoplasmic Functions of the m⁷Guanosine Cap

Leptomycin B, an Inhibitor of the Nuclear Export Receptor CRM1, Inhibits COX-2 Expression

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Involvement of CRM1, a nuclear export receptor, in mRNA export in mammalian cells and fission yeast

Cited by 41 publications

References 29 publications

1,25-Dihydroxyvitamin D3 suppresses exportin expression in human promyelocytic leukemia HL-60 cells

1,25-Dihydroxyvitamin D3 suppresses exportin expression in human promyelocytic leukemia HL-60 cells

Interaction of Eukaryotic Translation Initiation Factor 4G with the Nuclear Cap-Binding Complex Provides a Link between Nuclear and Cytoplasmic Functions of the m7Guanosine Cap

Leptomycin B, an Inhibitor of the Nuclear Export Receptor CRM1, Inhibits COX-2 Expression

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Interaction of Eukaryotic Translation Initiation Factor 4G with the Nuclear Cap-Binding Complex Provides a Link between Nuclear and Cytoplasmic Functions of the m⁷Guanosine Cap