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Cancer and the Nuclear Pore Complex

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Cancer and the Nuclear Pore Complex Cancer and the Nuclear Pore Complex Dan N. Simon and Michael P. Rout Abstract The nuclear pore complex (NPC) mediates traffi cking between the cyto- plasm and nucleoplasm. It also plays key roles in other nuclear processes such as chromatin silencing, transcriptional regulation, and DNA damage repair. Nucleoporins, the structural components of the NPC, have been linked to a multi- tude of cancers through chromosomal translocations generating fusion proteins, changes in protein expression levels, and single point mutations. Only a small num- ber of nucleoporins have been linked to tumorigenesis thus far, and these proteins— Nup62, Nup88, Nup98, Nup214, Nup358/RanBP2, and Tpr—line the traffi cking pathway and are particularly associated with mRNA export. Overexpression of sev- eral associated nuclear export factors, most also involved in various stages of mRNA export, has been linked to cancers as well. Some oncogenic nucleoporin mutants are mislocalized to either the cytoplasm or nucleoplasm while others are incorporated into the NPC, and in all these cases they are thought to misregulate signaling path- ways and transcription through either altered or diminished nucleoporin functional- ity. Intriguingly, many viruses target the same cancer-linked nucleoporins, often causing their degradation or mislocalization, implying that these viruses exploit some of the same weaknesses as the oncogenic defects. Keywords Nuclear envelope • Nuclear pore complex • Nucleoporin • Cancer • Leukemia • Tpr • Nup62 • Nup88 • Nup98 • Nup214 • Nup358/RanBP2 • Virus D. N. Simon • M. P. Rout (*) The Laboratory of Cellular and Structural Biology , The Rockefeller University , New York , NY 10065 , USA e-mail: [email protected]; [email protected] E.C. Schirmer and J.I. de las Heras (eds.), Cancer Biology and the Nuclear Envelope, 285 Advances in Experimental Medicine and Biology 773, DOI 10.1007/978-1-4899-8032-8_13, © Springer Science+Business Media New York 2014 286 D.N. Simon and M.P. Rout Abbreviations NPC Nuclear pore complex NE Nuclear envelope Tpr Translocated promoter region NLS Nuclear localization signal HGFR Hepatocyte growth factor receptor NTrk1 Neurotrophic tyrosine receptor kinase 1 FGFR1 Fibroblast growth factor receptor 1 EMS 8p11 myeloproliferative syndrome AML Acute myeloid leukemia AUL Acute undifferentiated leukemia MDS Myelodysplastic syndrome T-ALL T-cell acute lymphoblastic leukemia IMT Infl ammatory myofi broblastic tumor Alk Anaplastic lymphoma kinase B-ALL B-cell acute lymphoblastic leukemia CML Chronic myelogenous leukemia CMML Chronic myelomonocytic leukemia JMML Juvenile myelomonocytic leukemia eIF4E Eukaryotic initiation factor 4E TMEV Theiler’s murine encephalomyelitis virus VSV Vesicular stomatitis virus HIV-1 Human immunodefi ciency virus Introduction The nuclear envelope (NE), a double membrane extension of the ER, separates the nucleoplasm from the cytoplasm. Embedded within pores in the NE (termed nuclear pores) are nuclear pore complexes (NPCs). The NPC is arguably the largest multi- protein complex in eukaryotic cells (60–120 MDa in human cells) with an evolu- tionarily conserved eightfold structural symmetry [ 1 – 4 ]. Each NPC is organized around a core composed of eight spokes joined by rings that surround the central transport channel (Fig. 1 ). A single NPC is comprised of multiple copies of ~30 different proteins, termed nucleoporins, which are made up from a limited set of structural domains that includes α-helices, β-propellers, (Phe-Gly) FG repeats, WD domains, and transmembrane domains [ 3 – 5 ]. Despite much progress, we still have neither a high-resolution structure for the NPC, nor a full picture of the many vari- ants on this structure that are suspected between different organisms and tissues [ 4 ]. The primary, and perhaps best characterized, function of the NPC is to mediate the passive exchange of small molecules and the active transport of macromolecules between the nucleoplasm and cytoplasm. FG repeat-containing nucleoporins form an intrinsically disordered barrier in the central transport channel that, through a still Cancer and the Nuclear Pore Complex 287 a Cytoplasmic Filaments Core Scaffold Cytoplasmic Central Tube Nucleoporins FG Nucleoporins Central Spoke Inner Ring Outer Ring FG Nucleoporins Outer Nuclear Membrane Nuclear Inner Nuclear Envelope Membrane Transmembrane Ring Linker mRNP Remodeling Factors Nucleoporins mRNP Export Factors Exporting mRNP Nuclear mRNP Coating Factors FG Nucleoporins b Nuclear Basket Cancers Viruses IMT, EMS, Entero, Adeno, colon Herpes, HIV Cancers Viruses AML, MDS, Entero, Cardio, Cancers Viruses Nup358 T-ALL, CML, Influenza, VSV AML, AUL, Entero, Adeno, CMML, JMML, Nup214 MDS, T-ALL, Herpes, Cardio liver B-ALL Nup88 Nup98 Cancers Nup62 Cancers Viruses Ovary, stomach, colon, Ovary Entero, Adeno, liver, breast, prostate, Cardio, Pox, lung and others EB, HIV Nup62 Cancers Nup98 EMS, osteosarcoma, thyroid, colon Tpr Cancers Viruses VSV Rae1 Breast Cancers TREX Lung, colon, ovary, eIF4E thyroid, skin, testis, breast and others Cancers Lung, colon, breast, pancreas, bladder, brain, thyroid and others Fig. 1 Structure of the nuclear pore complex. ( a ) Each nuclear pore complex is a cylindrical structure comprised of eight spokes surrounding a central tube that connects the nucleoplasm and cytoplasm. The outer and inner nuclear membranes of the nuclear envelope join to form grommets, termed nuclear pores, in which the NPC sits. The NPC is anchored to the nuclear envelope by a transmembrane ring structure that connects to the core scaffold and comprises inner ring and outer ring elements. Linker nucleoporins help anchor the FG nucleoporins such that they line and fi ll the central tube. NPC- associated peripheral structures consist of cytoplasmic fi laments and the nuclear basket which mediate assembly and export of mRNP complexes. ( b ) The nuclear pore complex highlighting nucleoporins and mRNP export factors linked to cancers and viral infections. Adapted from [ 3 ] largely undetermined mechanism, impedes the passage of nonspecifi c macromole- cules while mediating the passage of FG repeat-binding soluble transport factors (most falling into a family of chaperones termed karyopherins, or importins and exportins) carrying their specifi c cognate cargo macromolecules through the NPC [ 3 , 6 ]. A gradient of the GTPase Ran, maintained by Ran cofactors, determines trans- port directionality by triggering the release of cargoes on the correct side of the NE [ 7 ]. Peripheral fi laments, formed by a subset of nucleoporins, emanate from the core structure into both the nucleoplasm and cytoplasm—and though they too play a role in transport, they also connect the NPC to numerous other cellular processes. On the 288 D.N. Simon and M.P. Rout cytoplasmic side, the fi laments are mostly disorganized and play a vital role in medi- ating traffi c through the NPC [ 3 , 6 ]; they couple mRNA export to translation initia- tion at ribosomes [ 8 ] and connect the NPC to the cytoskeleton [ 9 – 11 ]. The nuclear fi laments appear more structured, forming a basket-like structure. This basket plays key roles in transport regulation, in particular the assembly and proofreading of mRNP (messenger ribonucleoprotein) complexes prior to export. It also connects RNA export with DNA maintenance and transcriptional regulation, organizing com- plexes in the vicinity of the NPC that control DNA damage repair, chromatin silenc- ing and the transcriptional activation of many genes [ 12 – 15 ]. However, the molecular mechanisms of these NPC-associated processes are still largely unresolved. The NPC is therefore essential not only to regulating transport between the nucleo- plasm and cytoplasm but also to controlling genome organization and expression. These central cellular roles make it unsurprising—in retrospect—that the NPC has been linked with many diseases. These especially include cancers (Fig. 1 ). Nucleoporins have been directly implicated in cancers via three routes: chromosomal translocations generating fusion proteins; changes in protein expression levels; and single point mutations. Although found associated with cancers, whether or not many of these fusions and mutations are the primary cause or a downstream consequence of the disease, or are directly or indirectly linked to the processes of oncogenesis, remains unclear. Additionally, many viruses target NPC components, clearly facilitat- ing viral infections and even sometimes also leading to oncogenesis. As viruses have been termed “nature’s cell biologists,” it seems likely that they are exploiting some of the same weaknesses as the oncogenic defects. The involvement of NPC components in cancer has been described in great detail in several recent reviews [4 , 16 – 21 ], here, we will give a brief overview of these rapidly burgeoning areas of investigation, focussing on those nucleoporins particularly implicated in these diseases. T p r Translocated Promoter Region (Tpr) is a ~270 kDa protein that forms the bulk of the NPC nuclear basket. With Nup153 and other partners, it forms NPC-linked fi laments that extend into the nuclear interior [ 22 ]. Tpr and the various macromolecular com- plexes it recruits also maintain chromatin-free “channels” near the NPC, mediate export of proteins and mRNA, regulate telomere length and the mitotic spindle check- point, and help organize both the nuclear peripheral epigenetic silencing of some genes and the regulated transcriptional activation of others [ 13 , 23 – 30 ]. The N-terminal coiled-coil
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