Abstract
Nuclear pore complexes (NPCs) are the sole gateways between the nucleus and the cytoplasm of eukaryotic cells and they mediate all macromolecular trafficking between these cellular compartments. Nucleocytoplasmic transport is highly selective and precisely regulated and as such an important aspect of normal cellular function. Defects in this process or in its machinery have been linked to various human diseases, including cancer. Nucleoporins, which are about 30 proteins that built up NPCs, are critical players in nucleocytoplasmic transport and have also been shown to be key players in numerous other cellular processes, such as cell cycle control and gene expression regulation. This review will focus on the three nucleoporins Nup98, Nup214, and Nup358. Common to them is their significance in nucleocytoplasmic transport, their multiple other functions, and being targets for chromosomal translocations that lead to haematopoietic malignancies, in particular acute myeloid leukaemia. The underlying molecular mechanisms of nucleoporin-associated leukaemias are only poorly understood but share some characteristics and are distinguished by their poor prognosis and therapy outcome.
Highlights
NUP98 and NUP214 rearrangements share some common characteristics, such as HOXA activation and cooperation with the FLT3-ITD kinase, which may account for the impaired differentiation of the haematopoietic precursor cells and their uncontrolled proliferation
As Nup98, Nup214, and Nup358 are all somewhat important for protein and/or mRNA export, it will be interesting to see if their rearrangements lead to similar defects in nuclear export, which may account for the marked similarities in the clinical features in the hematopoietic malignancies associated with these three nucleoporins
Of particular interest in this context might be their link to the nuclear export receptor CRM1, which appears to play an important role in the aetiology of acute myeloid leukaemia (AML)
Summary
The nuclear envelope (NE) serves as a boundary that separates nuclear and cytoplasmic compartments to protect the genome This compartmentalization necessitates the transport of RNAs and proteins across the NE and this bidirectional macromolecular trafficking occurs through nuclear pore complexes (NPCs) [1, 2]. Transmembrane proteins, which in metazoans are comprised of gp210, Ndc, and POM121, anchor the NPC to the NE These nucleoporins reside at the boundary between the central framework and the pore membrane (Figure 1(c)). The scaffold of the NPC is made of nucleoporins containing α-helical solenoid and β-propeller fold motifs This group of nucleoporins includes the Nup107160 complex, which represents the major constituent of the cytoplasmic and the nuclear ring moieties [10, 30, 31] as well as the Nup complex, which is located towards the central pore of the NPC (Figure 1(c)). HOXA9 activation is a prevalent but not a uniform hallmark of nucleoporin-associated haematopoietic malignancies
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