Gene Section Review Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 228 Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS XPO1 (exportin 1 (CRM1 homolog, yeast)) Alessandra Ruggiero, Maria Giubettini, Patrizia Lavia CNR (National Research Council), Institute of Molecular Biology and Pathology, c/o Sapienza University of Rome, via degli Apuli 4, 00185 Rome, Italy (AR, MG, PL) Published in Atlas Database: November 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/XPO1ID44168ch2p15.html DOI: 10.4267/2042/47285 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Other names: CRM1, DKFZp686B1823, emb HGNC (Hugo): XPO1 Location: 2p15 Note The human XPO1/hCRM1 gene is localized on the 2p16 region (Fornerod et al., 1997a). 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). Protein 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).