XPO1

Official Full Name

exportin 1

Organism

Homo sapiens

GeneID

7514

Background

This cell-cycle-regulated gene encodes a protein that mediates leucine-rich nuclear export signal (NES)-dependent protein transport. The protein specifically inhibits the nuclear export of Rev and U snRNAs. It is involved in the control of several cellular processes by controlling the localization of cyclin B, MPAK, and MAPKAP kinase 2. This protein also regulates NFAT and AP-1. [provided by RefSeq, Jan 2015]

Synonyms

emb; CRM1; exp1; CRM-1;

Bio Chemical Class

Eukaryotic nuclear pore complex

Protein Sequence

MPAIMTMLADHAARQLLDFSQKLDINLLDNVVNCLYHGEGAQQRMAQEVLTHLKEHPDAWTRVDTILEFSQNMNTKYYGLQILENVIKTRWKILPRNQCEGIKKYVVGLIIKTSSDPTCVEKEKVYIGKLNMILVQILKQEWPKHWPTFISDIVGASRTSESLCQNNMVILKLLSEEVFDFSSGQITQVKSKHLKDSMCNEFSQIFQLCQFVMENSQNAPLVHATLETLLRFLNWIPLGYIFETKLISTLIYKFLNVPMFRNVSLKCLTEIAGVSVSQYEEQFVTLFTLTMMQLKQMLPLNTNIRLAYSNGKDDEQNFIQNLSLFLCTFLKEHDQLIEKRLNLRETLMEALHYMLLVSEVEETEIFKICLEYWNHLAAELYRESPFSTSASPLLSGSQHFDVPPRRQLYLPMLFKVRLLMVSRMAKPEEVLVVENDQGEVVREFMKDTDSINLYKNMRETLVYLTHLDYVDTERIMTEKLHNQVNGTEWSWKNLNTLCWAIGSISGAMHEEDEKRFLVTVIKDLLGLCEQKRGKDNKAIIASNIMYIVGQYPRFLRAHWKFLKTVVNKLFEFMHETHDGVQDMACDTFIKIAQKCRRHFVQVQVGEVMPFIDEILNNINTIICDLQPQQVHTFYEAVGYMIGAQTDQTVQEHLIEKYMLLPNQVWDSIIQQATKNVDILKDPETVKQLGSILKTNVRACKAVGHPFVIQLGRIYLDMLNVYKCLSENISAAIQANGEMVTKQPLIRSMRTVKRETLKLISGWVSRSNDPQMVAENFVPPLLDAVLIDYQRNVPAAREPEVLSTMAIIVNKLGGHITAEIPQIFDAVFECTLNMINKDFEEYPEHRTNFFLLLQAVNSHCFPAFLAIPPTQFKLVLDSIIWAFKHTMRNVADTGLQILFTLLQNVAQEEAAAQSFYQTYFCDILQHIFSVVTDTSHTAGLTMHASILAYMFNLVEEGKISTSLNPGNPVNNQIFLQEYVANLLKSAFPHLQDAQVKLFVTGLFSLNQDIPAFKEHLRDFLVQIKEFAGEDTSDLFLEEREIALRQADEEKHKRQMSVPGIFNPHEIPEEMCD

Open

Disease

Acute myeloid leukaemia, Brain cancer, Colorectal cancer, Diffuse large B-cell lymphoma, Liposarcoma, Multiple myeloma, Myelodysplastic syndrome, Prostate cancer, Solid tumour/cancer, Stomach cancer

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

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Detailed Information

Exportin 1, also known as CRM1, is a member of the karyopherin-β nuclear transport protein family and serves as a primary nuclear export receptor, mediating the transport of over 200 proteins and multiple RNAs between the nucleus and cytoplasm. Its function depends on the Ran GTPase cycle: within the nucleus, XPO1 binds Ran-GTP and cargo proteins containing a hydrophobic nuclear export signal (NES), forming a trimeric complex. This complex translocates through the nuclear pore into the cytoplasm, where hydrolysis of Ran-GTP to Ran-GDP triggers complex dissociation and cargo release. Key cargoes include tumor suppressor proteins, such as p53, FOXO3A, and IκB, whose nuclear retention can induce apoptosis or cell cycle arrest; growth regulators, including cyclin B1 and MAPK, whose abnormal cytoplasmic localization promotes proliferative signaling; and viral RNAs and proteins, such as HIV-1 Rev and influenza nucleoprotein, which rely on XPO1 for viral assembly. Under physiological conditions, XPO1 maintains the dynamic balance of transcription factors, participates in NFAT-mediated immune responses and AP-1-driven inflammation, and regulates U3 snoRNA transport from Cajal bodies to the nucleolus, influencing ribosome biogenesis.

Figure 1. Architecture of CRM1.(Ferreira BI, et al., 2020)

Pathological Roles and Disease Associations

XPO1 is commonly overexpressed or mutated in malignancies, leading to nuclear depletion of tumor suppressor proteins. In hematologic cancers, overexpression of XPO1 increases the nuclear export of proteins such as p53 and IKAROS, contributing to chemoresistance. In certain lymphomas, hotspot mutations in XPO1 enhance substrate affinity, accelerate nuclear export of inhibitory proteins, and promote survival signaling. Beyond oncology, XPO1 mediates nuclear export of viral proteins, assisting viruses like SARS-CoV-2 in evading host antiviral responses. High XPO1 expression also serves as a hub for therapeutic resistance; for instance, in multiple myeloma, it drives nuclear export of glucocorticoid receptors, reducing the effectiveness of hormone therapy, while retaining pro-survival BCL-2 family members in the nucleus, suppressing apoptosis.

Figure 2. Function of CRM1-mediated export and its significance in cancer. (Mathew C, et al., 2017)

Targeted Therapy and Clinical Translation

Selinexor is the first oral selective inhibitor of XPO1 (SINE class), covalently binding Cys528 within the NES groove to achieve functional inhibition. In hematologic malignancies, selinexor has been approved for use in combination therapies for relapsed or refractory multiple myeloma, demonstrating significant response rates and progression-free survival benefits. Its application in solid tumors remains challenging due to dose-limiting toxicities, although maintenance therapy has shown potential in certain cancers. Novel combination strategies are under investigation, including enhancing immunotherapy by promoting nuclear retention of transcription factors involved in anti-tumor immunity and mitigating viral-induced inflammation in severe infections. Future directions focus on developing irreversible XPO1 inhibitors with reduced toxicity and using NES-based predictive models to identify patient populations likely to benefit most.

Reference

Ferreira BI, Cautain B, Grenho I, Link W. Small Molecule Inhibitors of CRM1. Front Pharmacol. 2020 May 7;11:625.
Mathew C, Ghildyal R. CRM1 Inhibitors for Antiviral Therapy. Front Microbiol. 2017 Jun 28;8:1171.

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