Nuclear pore proteins and cancer - PubMed (original) (raw)

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Nuclear pore proteins and cancer

Songli Xu et al. Semin Cell Dev Biol. 2009 Jul.

Abstract

Nucleocytoplasmic trafficking of macromolecules, a highly specific and tightly regulated process, occurs exclusively through the nuclear pore complex. This immense structure is assembled from approximately 30 proteins, termed nucleoporins. Here we discuss the four nucleoporins that have been linked to cancers, either through elevated expression in tumors (Nup88) or through involvement in chromosomal translocations that encode chimeric fusion proteins (Tpr, Nup98, Nup214). In each case we consider the normal function of the nucleoporin and its translocation partners, as well as what is known about their mechanistic contributions to carcinogenesis, particularly in leukemias. Studies of nucleoporin-linked cancers have revealed novel mechanisms of oncogenesis and in the future, should continue to expand our understanding of cancer biology.

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Figures

Figure 1

Figure 1. Structural organization of the Nuclear Pore Complex

Left: a cutaway representation of the organization of the NPC with the major structural elements indicated. Three of the eight repeating segments that give the NPC 8-fold rotational symmetry are illustrated. Right: Schematic of nucleoporin subcomplexes and approximate position within the NPC. Substructures are color coded to match the left side of the panel.

Figure 2

Figure 2. Nucleoporin structure and rearrangement following chromosomal translocations

The four nucleoporins discussed are depicted with major structural elements, along with their translocation partners, if applicable, and the structure of the resulting chimeric fusion proteins. Abbreviations: β-prop, β-propeller; c-c, coiled-coil; RTK, receptor tyrosine kinase; P/S, proline, serine rich; TM, transmembrane; JM, juxtamembrane; HD, homeodomain; BD, binding domain; Ub, ubiquitination; P, phosphorylation.

Figure 3

Figure 3. Model for Nup98 fusions

Nup98 fusion proteins are proposed to interact with chromatin directly through their homeodomain as depicted here or indirectly through the binding activity of otherfusion partners, e.g. NSD1 as part of a histone methyltransferase complex. The FG/GLFG repeat domain recruits chromatin modifying complexes such as CBP/p300 or HDAC1 which leads to altered transcription of target genes. The basis for target gene selection is not understood.

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