Disease relevance of XPO1

• Human immunodeficiency virus type 1 (HIV-1) Rev contains a leucine-rich nuclear export signal that is essential for its nucleocytoplasmic export mediated by hCRM1 [1].
• For example, the human immunodeficiency virus RNA-binding protein Rev associates with the soluble cellular export receptor CRM 1 (exportin 1), which mediates nucleocytoplasmic translocation of Rev-HIV RNA complexes through the nuclear pore [2].
• Association with the cellular export receptor CRM 1 mediates function and intracellular localization of Epstein-Barr virus SM protein, a regulator of gene expression [2].
• Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles [3].
• Nuclear targeting of adenovirus type 2 requires CRM1-mediated nuclear export [4].

Psychiatry related information on XPO1

• Administration of both the high and low doses of S179D-PRL infused into the lateral ventricle (Exp 1) or MPOA (Exp 2) significantly delayed the onset of maternal behavior [5].
• Results of Exp-1 and Exp-2 indicated that tiagabine can reduce appetitive behavior for ethanol reward with no evidence of tolerance upon chronic exposure [6].

High impact information on XPO1

• We show that DDX3 is a nucleo-cytoplasmic shuttling protein, which binds CRM1 and localizes to nuclear membrane pores [7].
• In vivo, PHAX is required for U snRNA export but not for CRM1-mediated export in general [8].
• Conversely, leptomycin B, a cytotoxin that is shown to bind to CRM1 protein, specifically inhibits the nuclear export of Rev and U snRNAs [9].
• In vitro, CRM1 forms a leptomycin B-sensitive complex involving cooperative binding of both RanGTP and the nuclear export signal (NES) from either the Rev or PKI proteins [9].
• CRM1 is distantly related to receptors that mediate nuclear protein import and was previously shown to interact with the nuclear pore complex [9].

Chemical compound and disease context of XPO1

• Two distinct inhibitors of the nuclear export factor CRM1, leptomycin B (LMB) and ratjadone A (RJA) or CRM1-siRNAs blocked adenovirus infection, arrested cytoplasmic transport of viral particles at the microtubule-organizing center or in the cytoplasm and prevented capsid disassembly and nuclear import of the viral genome [4].
• Fractionation showed that wild-type and truncated APC from colon cancer cells were primarily cytoplasmic, but increased in the nucleus after leptomycin B treatment, consistent with CRM1-dependent nuclear export [10].
• A methionine-rich domain mediates CRM1-dependent nuclear export activity of Borna disease virus phosphoprotein [11].
• We analysed the corresponding hCRM1 coding regions by RT-PCR and sequencing in a panel of ten tumour cell lines, including three ovarian lines resistant either to cisplatin or paclitaxel, or to both and one MDR breast cancer cell line with nuclear accumulation of the transcription factor YB-1 [12].

Biological context of XPO1

• We propose that hCRM1 is a soluble nuclear transport factor that interacts with the NPC [13].
• Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression [14].
• The zinc finger cluster domain of RanBP2 is a specific docking site for the nuclear export factor, exportin-1 [15].
• We propose that Nup358 provides both a platform for rapid disassembly of CRM1 export complexes and a binding site for empty CRM1 recycling into the nucleus [16].
• Overexpression of the C-terminal FG-repeat region of CAN, which contains the binding site for hCRM1, caused sequestering of hCRM1 in the nucleoplasm and was sufficient to inhibit cell growth and to induce apoptosis [17].

Anatomical context of XPO1

• Our results are consistent with the hypothesis that the Ran-Crm1 complex may promote a local enrichment of NPM on centrosomes, thereby preventing centrosome reduplication [18].
• We recently developed an assay in which nuclear export of the shuttling transcription factor NFAT (nuclear factor of activated T cells) can be reconstituted in permeabilized cells with the GTPase Ran and the nuclear export receptor CRM1 [19].
• A role for RanBP1 in the release of CRM1 from the nuclear pore complex in a terminal step of nuclear export [19].
• In CAN-/- mouse embryos lacking CAN, hCRM1 remained in the nuclear envelope, suggesting that this protein can also bind to other repeat-containing nucleoporins [13].
• After preincubation of permeabilized cells with a Ran mutant that cannot hydrolyze GTP (RanQ69L), cytosol supports NFAT export, but CRM1 and Ran alone do not [19].

Associations of XPO1 with chemical compounds

• Deletion of this NES or treatment with the CRM1-specific inhibitor leptomycin B leads to overall nuclear accumulation of merlin isoforms missing exon 2 [20].
• Nucleocytoplasmic transfer of the NF2 tumor suppressor protein merlin is regulated by exon 2 and a CRM1-dependent nuclear export signal in exon 15 [20].
• Ran-binding protein 3 links Crm1 to the Ran guanine nucleotide exchange factor [21].
• CRM1/Exportin1 mediates the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES) by forming a cooperative ternary complex with the NES-bearing substrate and the small GTPase Ran [22].
• Residues critical for NES recognition are identified adjacent to the cysteine residue targeted by leptomycin B (LMB), a specific CRM1 inhibitor [22].

Physical interactions of XPO1

• In contrast, the export receptor CRM1 is predominantly bound to TMG-capped U3 species [23].
• We find that NXT1 binds directly to Crm1, and that the interaction is sensitive to the presence of Ran-GTP [24].
• CRM1 recognizes a specific amino acid sequence located within the DNA-binding domain of STAT1 [25].
• Neither Nup153 fragment affected binding of the export receptor Crm1 at the nuclear rim [26].
• Like HIV-1 Rev, K-Rev binds to both the Crm1 nuclear export factor and to a cis-acting viral RNA target to activate nuclear export of unspliced RNAs [27].

Enzymatic interactions of XPO1

• Results indicate that STAT1 can be dephosphorylated in the nucleus and actively exported by the chromosome region maintenance 1 (CRM1) export receptor [25].

Regulatory relationships of XPO1

• These observations demonstrate that INI1 has a masked NES that mediates regulated hCRM1/exportin1-dependent nuclear export and we propose that mutations that cause deregulated nuclear export of the protein could lead to tumorigenesis [28].
• RanBP3 stimulates export by enhancing the affinity of Crm1 for Ran.GTP and cargo [21].
• NXF3-dependent RNA export is therefore blocked by Crm1-specific inhibitors that do not affect TAP function [29].
• Thus, NXT1 regulates the Crm1-dependent export pathway through its direct interaction with Ran-GTP [30].
• We have identified the mechanism of XAP-2-induced cytoplasmic localization of the receptor and studied the potential cross-talk between CRM-1 and XAP-2 [31].

Other interactions of XPO1

• RanBP1 as well as Ran-binding domains of the cytoplasmic nucleoporin RanBP2 promote the release of CRM1 from the NPC [19].
• Full-length INI1 specifically associated with hCRM1/exportin1 in vivo and in vitro [28].
• Under the same conditions, the steady-state subcellular localization of other nuclear or cytoplasmic proteins and CRM1-mediated protein export are not detectably affected, indicating that the release of NXF1 into the cytoplasm and the inhibition of mRNA export are not due to a general defect in NPC function [32].
• RanBP3 could also promote binding of Crm1 to RCC1 in the presence of Ran [21].
• The RanQ69L preincubation leads to accumulation of CRM1 at the cytoplasmic periphery of the nuclear pore complex (NPC) in association with the p62 complex and Can/Nup214 [19].

Analytical, diagnostic and therapeutic context of XPO1

• We present a structural model of human CRM1 based on a combination of X-ray crystallography, homology modeling, and electron microscopy [22].
• Co-immunoprecipitation analysis showed that CRM1 preferentially interacted with S10D and S10E but not with S10A, suggesting that the phosphorylation of p27(Kip1) on Ser(10) is required for its binding to CRM1 and for its subsequent nuclear export [33].
• Using purified recombinant factors, we show by co-precipitation, gel mobility shift and protein footprinting assays that full-length Rev protein interacts directly with CRM1 in vitro independently of both the integrity of the characteristic leucine residues of the NES and the presence of the cytotoxin leptomycin B (LMB) [34].
• Molecular cloning and cell cycle-dependent expression of mammalian CRM1, a protein involved in nuclear export of proteins [35].
• Northern blot analyses with RNAs isolated from synchronized mammalian cells showed that the expression of mammalian CRM1 was initiated in late G1 and reached a peak at G2/M, although its protein level unchanged during the cell cycle [35].

References