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mRNA export and cancer

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Abstract Studies in the past several years highlight important features of the messenger RNA (mRNA) export process. For instance, groups of mRNAs acting in the same biochemical processes can be retained or exported in a coordinated manner thereby impacting on specific biochemistries and ultimately on cell physiology. mRNAs can be transported by either bulk export pathways involving NXF1/TAP or more specialized pathways involving chromosome region maintenance 1 (CRM1). Studies on primary tumor specimens indicate that many common and specialized mRNA export factors are dysregulated in cancer including CRM1, eukaryotic translation initiation factor 4E (eIF4E), HuR, nucleoporin 88, REF/Aly, and THO. This positions these pathways as potential therapeutic targets. Recently, specific targeting of the eIF4E‐dependent mRNA export pathway in a phase II proof‐of‐principle trial with ribavirin led to impaired eIF4E‐dependent mRNA export correlating with clinical responses including remissions in leukemia patients. Here, we provide an overview of these mRNA export pathways and highlight their relationship to cancer. WIREs RNA 2012, 3:13–25. doi: 10.1002/wrna.101 This article is categorized under: RNA in Disease and Development > RNA in Disease

A comparison of the NXF1/TAP and chromosome region maintenance 1 (CRM1) mRNA export pathways. In general, export of mRNA begins with a series of posttranscriptional modifications including: 5′‐capping, splicing, and addition of a 3′‐poly (A)‐tail.12 The TREX/THO complex with UAP56 associates with spliced mRNA.17,20 Depending on the cellular requirements, specific export factors are recruited in order to remodel the pre‐export mRNP prior to entering a dedicated export pathway. In the case of bulk mRNA export, UAP56 binds to REF/Aly which then recruits the TAP/NXF1‐p15 heterodimer.17,18,28 TAP‐p15 interacts with components of the nuclear pore complex (NPC) and serves as the export factor for bound mRNAs.29,30 Since REF/Aly is dispensable, other intermediate factors may serve as export adapters.26 DDX19/Dbp5 dissociates NXF1/TAP‐p15 from the nuclear rim and along with Gle1 and Inositol hexakisphosphate stimulate the release of the mRNA cargo in the cytoplasm.31–34 It is unknown whether DDX19/Dbp5‐Gle1 play a role in CRM1‐mediated export. Alternatively, factors recruited to the pre‐export mRNP can serve as adapters for different mRNA cargoes to enter a CRM1‐dependent pathway. For instance, factors containing a nuclear export signal (NES), APRIL and pp32 are proposed to act as a bridge between HuR and CRM1 to mediate the export of specific (AU‐rich) mRNAs.35 The NES containing NXF3 may serve as a tissue‐specific CRM1 adapter for the export of a specific mRNA, however, these mRNAs remain unknown.36 After splicing, mRNAs containing the 4E‐sensitivity element (4E‐SE) recruit eIF4E and LRPPRC to undergo CRM1‐mediated export.37 Whether LRPPRC is the sole adapter or if other adapters exist remains to be determined. Both NXF1 and CRM1 interact directly with the NPC for cargo export.

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Mechanism of Ran‐dependent CRM1 cargo release. Left panel: in the nucleus, CRM1 binds the nuclear export signal (NES) on the mRNP cargo together with RanGTP and RanBP3. RanBP3 is proposed to stabilize and select export complexes which are then translocated to the cytoplasm.45 In the cytoplasm, hydrolysis of RanGTP by RanGAP induces the dissociation of the complex. Upon re‐entry into the nucleus, RanGDP is then converted to RanGTP by the guanine nucleotide exchange factor RCC.46 The RanGTP/GDP gradient across the nuclear membrane creates directionality for the transport process. Right panel: RanBP1 and RanBP2/Nup 358 act as cofactors for RanGAP which can increase the rate of GTP hydrolysis and promotes dissociation of the CRM1‐RanGTP‐Cargo.47,48 Nup88 and Nup214 associate with the cytoplasmic ring and/or fibrils of the nuclear pore complex (NPC) and also bind to Nup358/RanBP2. Nup214 interaction with CRM1 and Nup358 provides a link between the export receptor and the cytoplasmic filament.5 Note that, bulk mRNA export is Ran independent. For bulk mRNA, Nup 214 interacts with DDX19/Dbp5 which is required to dissociate NXF1/TAP‐p15 from the nuclear rim.31 DDX19/Dbp5 associates with Gle1 and inositol hexakisophosphate (InsP6) and together facilitates the release of the mRNA cargo in the cytoplasm.32–34 It is unknown whether DDX19/Dbp5‐Gle1 play a role in CRM1‐mediated export. INM and ONM are the inner and outer nuclear membranes, respectively.

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