XPO1 (exportin 1 (CRM1 homolog, yeast))

2011-11-01   Alessandra Ruggiero , Maria Giubettini , Patrizia Lavia 

CNR (National Research Council), Institute of Molecular Biology, Pathology, c\\\/o Sapienza University of Rome, via degli Apuli 4, 00185 Rome, Italy

Identity

HGNC
LOCATION
2p15
LOCUSID
ALIAS
CRM-1,CRM1,emb,exp1
FUSION GENES

DNA/RNA

Transcription

The human XPO1/hCRM1 gene is transcribed in a cell cycle-dependent manner, with the onset of mRNA transcription taking place in late G1 phase and peaking in the G2/M phases of the cell cycle (Kudo et al., 1997). NFY/CBP, Sp1 and p53 transcription factors are reported to interact with the XPO1/hCRM1 gene promoter and play an important role in XPO1/hCRM1 promoter activity in transformed and cancer cells (van der Watt and Leaner, 2011).

Proteins

Note

A human protein, originally named CC112 based on its apparent molecular weight, was identified in a search for interacting partners of CAN/NUP214, a nucleoporin regarded as a proto-oncogenic factor. CAN was implicated in acute myeloid leukemia and in myelodysplastic syndrome (von Lindern et al., 1992) as part of the DEK-CAN fusion gene generated in the translocation t(6;9)(p23;q34). Another potentially oncogenic fusion protein involving CAN was identified in a patient with acute undifferentiated leukemia, in which case the t(6;9) yielded a SET-CAN fusion. Wild-type CAN is identical to the nucleoporin NUP214. CC112 was capable of interacting with both wild-type CAN/NUP214 and with both its fusion proteins, DEK-CAN and SET-CAN, suggesting potential roles in proliferation of cancer cells (Fornerod et al., 1996).

Description

The human XPO1/CRM1 protein is composed of 1071 aminoacidic residues with a molecular weight of 112 kDa (Fornerod et al., 1997b). It is a modular protein composed of several fuctional domains:
- The N-terminal region shares sequence similarity with importin β in a region called the CRIME domain (acronym for CRM1, importin beta etc.). This domain interacts with the GTPase RAN. In the GTP-bound form, RAN stabilizes export complex formed by CRM1 and NES-containing proteins.
- Most of the XPO1/CRM1 protein is composed of 19 HEAT repeat motifs. HEAT repeat 8 contains an acidic loop which cooperates with the CRIME domain in RANGTP binding.
- The central region of XPO1/CRM1 is involved in NES binding. Cys528, lying in this region, is specifically blocked by the inhibitor leptomycin B (LMB), which therefore blocks the export activity of XPO1/CRM1 (Wolff et al., 1997).
- The C-terminal region is thought to modulate the affinity of XPO1/CRM1 for its cargoes.

Structures
The structure of the region corresponding to residues 707-1034 (C-terminal region) was elucidated by X-ray crystallography (Petosa et al., 2004).
The structure of XPO1/CRM1 complexed to various NESs and to RANGTP has been solved (Güttler et al., 2010).

Expression

XPO1/CRM1 protein levels remain constant throughout the cell cycle (Kudo et al., 1997).

Localisation

Due to its function as a shuttling nuclear transport receptor between the nucleus and cytoplasm, the human XPO1/CRM1 protein is preferentially localized at the nuclear envelope in interphase cells (Kudo et al., 1997; Fornerod et al., 1997b). In the nucleus it can be detected in specific bodies called CRM1 nucleolar bodies (CNoBs). CNoBs depend on RNA polymerase I activity, suggesting a role in ribosome biogenesis (Ernoult-Lange et al., 2009).
In mitotic cells, a fraction of XPO1 is found at centrosomes (Forgues et al., 2003; Wang et al., 2005) and a substantial fraction localizes to the kinetochores (Arnaoutov et al., 2005).
Atlas Image
The plates show the subcellular localisation of CRM1 (detected by indirect immunofluorescence) in interphase and mitotic human HeLa cells. Upper row: an interphase cell showing CRM1 (in red in the left panel) within the nucleus and especially around the nuclear envelope, where it concentrates with a regular, punctuated pattern typical of the association with nuclear pore complexes. The nuclear shape is depicted in the upper right panel by staining the DNA with the fluorochrome 4,6-diamidino-2-phenylindole (DAPI, in blue). Lower row: a metaphase cell showing CRM1 (in red in the left panel) concentrating at the kinetochores (compare with the middle panel, where kinetochore proteins are stained using CREST antiserum and a blue-emitting secondary antibody). A CRM1 fraction is also visible at spindle poles (compare with the staining of the mitotic spindle microtubules using an antibody against alpha-tubulin, in green). The merged picture shows a 3.5x magnification of the overlay of all three images: CRM1 (red) lies at the interface between the kinetochores (blue) and the microtubules (green) projecting from opposite spindle poles.

Function

hCRM1 was found to interact stably in complexes containing not only NUP214/CAN (or its derivatives), but also another component of nuclear pores, the nucleoporin NUP88 (Fornerod et al., 1997b). These interactions hinted at a possible role of hCRM1 in nucleocytoplasmic transport. Further studies indeed demonstrated that hCRM1 acts as a nuclear export factor (reviewed by Fried and Kutaj, 2003; Hutten and Kehlenbach, 2007): it interacts with various classes of RNAs and with proteins carrying nuclear export signals (NES) (Fornerod et al., 1997c; Fukuda et al., 1997; Ossareh-Nazari et al., 1997), short aminoacidic stretches harbouring hydrophobic residues (general consensus LX(2-3)ΦX(2-3)LXΦ, where can be L, I, M or F), present in many shuttling proteins of cellular or viral origin, and transports these molecules out of the nucleus through nuclear pore complexes in a manner dependent on the GTPase RAN. The protein is therefore alternatively called either exportin-1 or XPO1, based on its function, or hCRM1, based on evolutionary conservation.
Regulated export of some shuttling proteins (e.g., p53, p27, STAT, NF-kB and many viral proteins) out of the nucleus is essential for regulated cell cycle and cell proliferation (reviewed by Fabbro and Henderson, 2003; Rensen et al., 2008). This has lead some authors to view nuclear export as a promising target process in cancer therapy (reviewed by Yashiroda and Yoshida, 2003; Turner and Sullivan, 2008).
Recent findings have revealed additional roles of XPO1/CRM1 in mitosis: first, an XPO1/CRM1 fraction regulates the localisation of nucleophosmin (NPM/B23), a regulator of centrosome duplication. XPO1/CRM1 is required to prevent centrosome overduplication and the formation of multipolar spindles (reviewed by Budhu and Wang, 2005; Ciciarello and Lavia, 2005). Second, a kinetochore-associated fraction of XPO1/CRM1 regulates the assembly of the so-called k-fibers, bundles of microtubules that stably connect the spindle poles to the kinetochores of mitotic chromosomes to ensure proper chromosome segregation (reviewed by Arnaoutov and Dasso, 2005; Ciciarello and Lavia, 2005; Dasso, 2006). Third, XPO1/CRM1 regulates survivin, a member of the chromosomal passenger complex with roles in chromosome segregation and apoptosis (reviewed by Knauer et al., 2007).
In synthesis, XPO1/CRM1 acts in control of cell proliferation, and affects loss of proliferation control in cancer cells, through several pathways: 1. as a nuclear export factor, it directly regulates the subcellular localisation, and hence the activity, of oncogenes and tumour suppressor proteins that contain nuclear export sequences; 2. it acts in control of the mitotic apparatus and chromosome segregation; 3. it influences the maintenance of nuclear and chromosome structure.

Homology

The human protein originally named CC112 showed homology to the Schizosaccharomyces pombe CRM1 protein, first identified for being implicated in the control of higher order chromosome structure: mutation of the coding gene was associated with the appearance of "deformed nuclear chromosome domains" in fission yeast conditional mutant strains. The gene product was therefore named CRM1 (chromosome region maintenance 1; Adachi and Yanagida, 1989). Based on this homology, the human protein name of CC112 was abandoned and the name hCRM1 was used.

Implicated in

Entity name
Ovarian cancer (Noske et al., 2008)
Prognosis
Increased nuclear (52.7%) and cytoplasmic (56.8%) expression of CRM1 were reported observed in carcinomas compared with borderline tumors and benign lesions. Cytoplasmic CRM1 expression significantly correlated with advanced tumor stage (P= 0.043), poorly differentiated carcinomas (P= 0.011) and high mitotic rate (P= 0.008). Nuclear CRM1 was significantly associated with high cyclooxygenase-2 (COX-2) expression (P= 0.002) and poor overall survival (P= 0.01). CRM1 was previously directly implicated in nuclear export of COX-2 (Jang et al., 2003). The study by Noske et al. (2008) suggests that elevated expression of CRM1 may be causal to COX-2 up-regulation, with direct clinical relevance.
Oncogenesis
CRM1 is highly expressed in ovarian carcinomas tissues and regulates export of COX-2.
Entity name
Osteosarcoma (Yao et al., 2009)
Prognosis
The CRM1 protein is reported to be expressed with increased abundance in osteosarcoma compared to non-tumour tissues (P= 0.037, 57 patients). High levels of CRM1 were significantly associated with increased serum levels of alkaline phosphatase (ALP, P= 0.001). In univariate analysis, a significant association between CRM1 expression and tumor size (P= 0.014), as well as histological grade (P= 0.003) was observed. In Kaplan-Meier survival analysis, high CRM1 expression was a significant prognostic indicator for poor progression-free survival (P= 0.016) as well as overall survival (P= 0.008). Multivariate analysis demonstrated that high expression of CRM1 was significantly related to shorter survival (95% CI, 1.27-5.39).
Oncogenesis
CRM1 is significantly increased in osteosarcoma compared with normal tissue.
Entity name
Cervical cancer (van der Watt et al., 2009)
Oncogenesis
CRM1 protein abundance is significantly increased in cervical cancer cells compared with normal tissue (P< 0.05). Inhibition of CRM1 by RNA interference resulted in increased cell death, associated with nuclear retention of p53, likely protecting p53 from degradation as the latter predominantly occurs in the cytoplasm.
Entity name
Pancreas cancer (Huang et al., 2009)
Prognosis
Increased expression abundance of CRM1 protein was detected in pancreatic cancer tissues (P= 0.0013, 69 patients at stages I and II). CRM1 expression correlates with increased levels of serum CEA (P= 0.002) and CA19.9 (P= 0.005), tumour size (P= 0.011), lymphadenopathy (P= 0.004) and metastasis (P= 0.0041). High CRM1 expression was a prognostic indicator for progression-free survival (PFS) (P= 0.0011) as well as overall survival (OS) (P= 0.004). The authors proposed that CRM1 be used as a prognostic parameter for poor PFS and OS (95% CI, 1.27-5.39).
Entity name
Glioma (Shen et al., 2009)
Prognosis
CRM1 overexpression is significantly associated with the pathological state (P= 0.001, 56 patients), with glioma tumour grade, with high expression of phospho-ser10p27 and with reduced overall abundance of p27.
Oncogenesis
Given the direct implication of CRM1 in nuclear export of p27, the data in this study suggest that increased CRM1 abundance yields increased cytoplasmic localisation of p27, which is probably targeted to degradation, leading to uncontrolled tumour growth. Phospho-ser10p27 may be resistant to CRM1-mediated nuclear export. High CRM1 and low p27 expression are associated with high grade glioma and high CRM1 protein expression is proposed as a prognostic factor of overall survival and poor outcome.

Bibliography

Pubmed IDLast YearTitleAuthors
26477651989Higher order chromosome structure is affected by cold-sensitive mutations in a Schizosaccharomyces pombe gene crm1+ which encodes a 115-kD protein preferentially localized in the nucleus and its periphery.Adachi Y et al
160822122005Ran-GTP regulates kinetochore attachment in somatic cells.Arnaoutov A et al
162940172005Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1.Budhu AS et al
160650642005New CRIME plots. Ran and transport factors regulate mitosis.Ciciarello M et al
170521802006Ran at kinetochores.Dasso M et al
189231372009Nucleocytoplasmic traffic of CPEB1 and accumulation in Crm1 nucleolar bodies.Ernoult-Lange M et al
125316922003Regulation of tumor suppressors by nuclear-cytoplasmic shuttling.Fabbro M et al
128610142003Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles.Forgues M et al
93231331997CRM1 is an export receptor for leucine-rich nuclear export signals.Fornerod M et al
145046562003Nucleocytoplasmic transport: taking an inventory.Fried H et al
93843861997CRM1 is responsible for intracellular transport mediated by the nuclear export signal.Fukuda M et al
209724482010NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.Güttler T et al
200038382009Prognostic value of CRM1 in pancreas cancer.Huang WY et al
173171852007CRM1-mediated nuclear export: to the pore and beyond.Hutten S et al
124685432003Leptomycin B, an inhibitor of the nuclear export receptor CRM1, inhibits COX-2 expression.Jang BC et al
173610972007Survivin's dual role: an export's view.Knauer SK et al
93680441997Molecular cloning and cell cycle-dependent expression of mammalian CRM1, a protein involved in nuclear export of proteins.Kudo N et al
183063892008Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer.Noske A et al
93119221997Evidence for a role of CRM1 in signal-mediated nuclear protein export.Ossareh-Nazari B et al
155743312004Architecture of CRM1/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex.Petosa C et al
185085022008The GTPase Ran: regulation of cell life and potential roles in cell transformation.Rensen WM et al
195748372009Expression of CRM1 in human gliomas and its significance in p27 expression and clinical prognosis.Shen A et al
189916272008CRM1-mediated nuclear export of proteins and drug resistance in cancer.Turner JG et al
160413682005Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication.Wang W et al
91902881997Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent mRNA.Wolff B et al
190824672009The expression of CRM1 is associated with prognosis in human osteosarcoma.Yao Y et al
126787772003Nucleo-cytoplasmic transport of proteins as a target for therapeutic drugs.Yashiroda Y et al
216838122011The nuclear exporter, Crm1, is regulated by NFY and Sp1 in cancer cells and repressed by p53 in response to DNA damage.van der Watt PJ et al
15491221992The translocation (6;9), associated with a specific subtype of acute myeloid leukemia, results in the fusion of two genes, dek and can, and the expression of a chimeric, leukemia-specific dek-can mRNA.von Lindern M et al

Other Information

Locus ID:

NCBI: 7514
MIM: 602559
HGNC: 12825
Ensembl: ENSG00000082898

Variants:

dbSNP: 7514
ClinVar: 7514
TCGA: ENSG00000082898
COSMIC: XPO1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000082898ENST00000401558O14980
ENSG00000082898ENST00000404992O14980
ENSG00000082898ENST00000406957O14980
ENSG00000082898ENST00000420673C9JV99
ENSG00000082898ENST00000422552C9JQ02
ENSG00000082898ENST00000428210F8WF71
ENSG00000082898ENST00000436018C9JF49
ENSG00000082898ENST00000437159H7BZC5
ENSG00000082898ENST00000443240C9J673
ENSG00000082898ENST00000449444C9IYM2
ENSG00000082898ENST00000451765C9JKM9
ENSG00000082898ENST00000457483C9IZS4

Expression (GTEx)

0
10
20
30
40
50
60
70
80
90
100

Pathways

PathwaySourceExternal ID
RNA transportKEGGko03013
RNA transportKEGGhsa03013
Ribosome biogenesis in eukaryotesKEGGko03008
Ribosome biogenesis in eukaryotesKEGGhsa03008
Influenza AKEGGko05164
Influenza AKEGGhsa05164
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
DiseaseREACTOMER-HSA-1643685
Infectious diseaseREACTOMER-HSA-5663205
HIV InfectionREACTOMER-HSA-162906
HIV Life CycleREACTOMER-HSA-162587
Late Phase of HIV Life CycleREACTOMER-HSA-162599
Rev-mediated nuclear export of HIV RNAREACTOMER-HSA-165054
Host Interactions of HIV factorsREACTOMER-HSA-162909
Interactions of Rev with host cellular proteinsREACTOMER-HSA-177243
Influenza InfectionREACTOMER-HSA-168254
Influenza Life CycleREACTOMER-HSA-168255
Export of Viral Ribonucleoproteins from NucleusREACTOMER-HSA-168274
NEP/NS2 Interacts with the Cellular Export MachineryREACTOMER-HSA-168333
Signal TransductionREACTOMER-HSA-162582
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases Activate ForminsREACTOMER-HSA-5663220
Signaling by TGF-beta Receptor ComplexREACTOMER-HSA-170834
TGF-beta receptor signaling activates SMADsREACTOMER-HSA-2173789
Downregulation of TGF-beta receptor signalingREACTOMER-HSA-2173788
Signaling by WntREACTOMER-HSA-195721
TCF dependent signaling in response to WNTREACTOMER-HSA-201681
Deactivation of the beta-catenin transactivating complexREACTOMER-HSA-3769402
Gene ExpressionREACTOMER-HSA-74160
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
HuR (ELAVL1) binds and stabilizes mRNAREACTOMER-HSA-450520
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G2-G2/M phasesREACTOMER-HSA-453274
G2/M TransitionREACTOMER-HSA-69275
Cyclin A/B1 associated events during G2/M transitionREACTOMER-HSA-69273
M PhaseREACTOMER-HSA-68886
Mitotic PrometaphaseREACTOMER-HSA-68877
Resolution of Sister Chromatid CohesionREACTOMER-HSA-2500257
Mitotic Metaphase and AnaphaseREACTOMER-HSA-2555396
Mitotic AnaphaseREACTOMER-HSA-68882
Separation of Sister ChromatidsREACTOMER-HSA-2467813

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA164712708Drugs For Treatment Of TuberculosisChemicalClinicalAnnotationassociatedPD30817003
PA164925725Toxic liver diseaseDiseaseClinicalAnnotationassociatedPD22341855, 29036176
PA166119041drug-induced liver injuryDiseaseClinicalAnnotationassociatedPD22341855, 29036176
PA443937Drug ToxicityDiseaseClinicalAnnotationassociatedPD30817003
PA445941TuberculosisDiseaseClinicalAnnotationassociatedPD30817003
PA450112isoniazidChemicalClinicalAnnotationassociatedPD22341855, 29036176

References

Pubmed IDYearTitleCitations
246868502014Genomic and molecular characterization of esophageal squamous cell carcinoma.168
193399692009Structural basis for leucine-rich nuclear export signal recognition by CRM1.130
230342822012Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.115
165527252006Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1.101
191170562009The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation.97
226771302012Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia.94
235887152014CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.93
151179712004Somatic hypermutation is limited by CRM1-dependent nuclear export of activation-induced deaminase.92
183063892008Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer.91
235649112013Prognostic impact and targeting of CRM1 in acute myeloid leukemia.85

Citation

Alessandra Ruggiero ; Maria Giubettini ; Patrizia Lavia

XPO1 (exportin 1 (CRM1 homolog, yeast))

Atlas Genet Cytogenet Oncol Haematol. 2011-11-01

Online version: http://atlasgeneticsoncology.org/gene/44168/xpo1