The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export

Neville, Megan C; Stutz, Françoise; Lee, Linda; Davis, Laura I.; Rosbash, Michael

doi:10.1016/s0960-9822(06)00335-6

Cited by 401 publications

(368 citation statements)

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“…The activities of these proteins are tightly regulated by their NESs. Chromosomal region maintenance 1 (CRM1), which belongs to the family of importin-related nuclear transport receptors, directly and specifically associates with the NES and mediates the nuclear export of protein containing NESs (Fornerod et al, 1997;Fukuda et al, 1997;Neville et al, 1997;Ossareh-Nazari et al, 1997;Stade et al, 1997;Haasen et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

et al. 2006

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Leptomycin B (LMB) is a Streptomyces metabolite that causes the specific inhibition of the nuclear export of proteins containing a nuclear export signal (NES). LMB was reported to inhibit cell cycle progression in fission yeast and mammalian cells, however, the mechanism underlying LMB-induced cell cycle arrest is still obscure. In this study, we found that in serum-starved NIH3T3 cells, LMB inhibited serum-induced cyclin D1 expression at the level of transcription. However, this inhibition was reversed by inhibitors of protein phosphatase 2A (PP2A). Furthermore, we found that PP2A accumulated in the nucleus upon treatment with LMB. The finding prompted us to identify the functional NES in PP2A catalytic subunit a. These results indicated that LMB inhibited the chromosomal region maintenance 1 (CRM1)-dependent nuclear export of PP2A, resulting in sustained dephosphorylation in the nucleus. Although phosphorylation of c-Jun at Ser-63 is required for activator protein 1 (AP-1)-dependent expression of cyclin D1, it decreased in LMBtreated cells compared to untreated cells. Moreover, the inhibitors of PP2A restored the levels of c-Jun phosphorylated at Ser-63. We propose that inhibition of cyclin D1 expression by LMB is mediated by the LMB-induced nuclear accumulation of PP2A, leading to sustained dephosphorylation of c-Jun at Ser-63, which leads to inactivation of the transcription of the AP-1-responsive cyclin D1 gene.

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Section: Introductionmentioning

confidence: 99%

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

et al. 2006

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“…Three previously known Xpo1 interaction partners (Yap1, Nup42, and Nup49) were identified, demonstrating the usefulness of the two-hybrid method for this purpose. Yap1 contains a nuclear export sequence of the leucine-rich type and acts as an export substrate for Xpo1 (76) whereas Nup42 and Nup49 (48) are structural components of the nuclear pore complex (NPC) through which all nucleocytoplasmic trafficking occurs (18,69). Sgm1, Sla2, Spc72, Ltv1, and Hpa3 represent novel interaction partners for Xpo1.…”

Section: Resultsmentioning

confidence: 99%

Nuclear Export Receptor Xpo1/Crm1 Is Physically and Functionally Linked to the Spindle Pole Body in Budding Yeast

Neuber

Franke

Wittstruck

et al. 2008

Molecular and Cellular Biology

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The spindle pole body (SPB) represents the microtubule organizing center in the budding yeast Saccharomyces cerevisiae. It is a highly structured organelle embedded in the nuclear membrane, which is required to anchor microtubules on both sides of the nuclear envelope. The protein Spc72, a component of the SPB, is located at the cytoplasmic face of this organelle and serves as a receptor for the ␥-tubulin complex. In this paper we show that it is also a binding partner of the nuclear export receptor Xpo1/Crm1. Xpo1 binds its cargoes in a Ran-dependent fashion via a short leucine-rich nuclear export signal (NES). We show that binding of Spc72 to Xpo1 depends on Ran-GTP and a functional NES in Spc72. Mutations in this NES have severe consequences for mitotic spindle morphology in vivo. This is also the case for xpo1 mutants, which show a reduction in cytoplasmic microtubules. In addition, we find a subpopulation of Xpo1 localized at the SPB. Based on these data, we propose a functional link between Xpo1 and the SPB and discuss a role for this exportin in spindle biogenesis in budding yeast.In eukaryotes, the movement of proteins and RNAs between the nucleus and the cytoplasm is an essential cellular process that is mediated by soluble transport receptors (26,52). In addition, the small GTPase Ran (Gsp1 in yeast) and its cytoplasmic and nuclear effectors are needed (12). Transport receptors involved in nuclear import reactions are usually termed importins, and they recognize their cargoes via a specific amino acid motif, the nuclear localization sequence, or NLS. By analogy, nuclear export reactions are mediated by so-called exportins. Xpo1 (also known as Crm1) was one of the first nuclear export receptors to be identified (23,27,50,64) and recognizes a short leucine-rich amino acid sequence on its cargo, called a nuclear export signal, or NES. Numerous export cargoes have now been identified for the mammalian Crm1 protein, including protein kinase A inhibitor PKI, p53, and the human immunodeficiency virus protein Rev (20,25,66). In addition, Crm1 is involved in the nuclear export of several classes of RNAs such as viral pre-mRNAs, ribosomal RNAs, and snRNAs (54). In contrast, few NES-containing proteins have been identified in Saccharomyces cerevisiae. Although the budding yeast Crm1 orthologue Xpo1 is involved in nuclear export of Hog1 (19), Yap1 (76), Ssb1 (62), Ace2 (36), and Prp40 (46), few of the NESs involved have been characterized at a molecular level.Recently, alongside its well-established role in nuclear export, mammalian Crm1 was shown to be involved in the control of centrosome duplication (71). Centrosomes function as microtubule (MT) organizing centers in mammalian somatic cells and direct the formation of a bipolar spindle during mitosis (reviewed in reference 6). In another study, Crm1 was found to bind to kinetochores, complex protein assemblies that are needed to establish the attachment of MTs to chromatin (4). These studies point to an unanticipated role of the exportin Crm1 in control of spin...

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“…Dissociation of the complex is likely to involve the exchange of GTP for GDP on the Ran moiety. It is unclear whether the returning importins carry a di erent cargo back to the cytoplasm, but nuclear export-speci®c importin b family members have been identi®ed that mediate the transport from the nucleus to the cytoplasm of, for example, tRNA (Arts et al, 1998a,b;Hellmuth et al, 1998;Kutay et al, 1998) or of proteins that contain a leucine-rich Nuclear Export Signal (NES); (Fornerod et al, 1997;Fukuda et al, 1997a;Neville et al, 1997;Ossareh-Nazari et al, 1997;Stade et al, 1997). Again, release of the export cargo at the cytoplasmic face of the nuclear pore is likely to involve the hydrolysis of GTP that is bound to the Ran component of the export complex (Bischo and Schlenstedt et al, 1997;Kehlenbach et al, 1999).…”

Section: Nuclear Transportmentioning

confidence: 99%

Regulated nuclear localization of stress-responsive factors: how the nuclear trafficking of protein kinases and transcription factors contributes to cell survival

Ferrigno

Silver

1999

Oncogene

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The details of nuclear transport mechanisms are emerging rapidly, largely through work with model organisms. Here, we brie¯y describe these advances, with an emphasis on the remaining challenges. We then address the nuclear transport of some high pro®le cellular regulators, including p53 and the proto-oncogene PKB/Akt. We discuss the mechanisms that contribute to the di erential subcellular localization of these proteins. Finally, we analyse the provocative patterns that emerge from our overview.

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The importin-beta family member Crm1p bridges the interaction between Rev and the nuclear pore complex during nuclear export

Abstract: We conclude that Crm1p interacts with the Rev NES and nuclear pore proteins during delivery of cargo to the nuclear pore complex. Our findings also agree well with current experiments on Crm1p orthologs in Schizosaccharomyces pombe and in vertebrate systems.

Cited by 401 publications

References 50 publications

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression

Nuclear Export Receptor Xpo1/Crm1 Is Physically and Functionally Linked to the Spindle Pole Body in Budding Yeast

Regulated nuclear localization of stress-responsive factors: how the nuclear trafficking of protein kinases and transcription factors contributes to cell survival

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