Abstract
Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors.
Highlights
The cytoplasm and the nucleoplasm are separated by the nuclear envelope in eukaryotic cells.Spatially segregation of essential cellular processes requires tight control of large molecule exchange such as RNAs, proteins, or ribonucleoprotein particles through this double membrane
The transfer of macromolecules such as proteins through the nuclear pore complexes (NPC) is strictly controlled by processes that involve a number of nuclear transport receptors (NTRs) called karyopherins or importins/exportins
The Ras-related small GTPase Ran regulates the conformation of importin β and determines molecular interactions between the nuclear transport receptor and its cargo protein [20]
Summary
The cytoplasm and the nucleoplasm are separated by the nuclear envelope in eukaryotic cells. Segregation of essential cellular processes requires tight control of large molecule exchange such as RNAs, proteins, or ribonucleoprotein particles through this double membrane. The gatekeepers of these processes are nuclear pore complexes (NPC) which are large membrane-spanning protein complexes embedded in the nuclear envelope and consisting of multiple copies of approximately. They allow the passive passage of ions and molecules across the nuclear envelope, while building a barrier to free diffusion for molecules larger than a Stokes radius of ~ 2.5 nm, corresponding to a protein mass of approximately 35–40 kDa. The transfer of macromolecules such as proteins through the NPCs is strictly controlled by processes that involve a number of nuclear transport receptors (NTRs) called karyopherins or importins/exportins. We summarize and discuss specific and general inhibitors of protein nuclear transport receptors and their clinical implications
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