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Cell Division: Nuclear Import/Export Inhibitors | | | 
Proteins required for nuclear functions are specifically transported from the cytoplasm into the nucleus. In general, proteins larger than 25 nm in diameter (~30 kDa) can only enter the nucleus in an energy-dependent process, which calls for the participation of a variety of soluble import factors. Trafficking between the nucleus and the cytoplasm occurs via the nuclear pore complexes (NPCs). NPCs are large supramolecular assemblies of ~125-mDa and contain about 100 polypeptides embedded in the double-membrane nuclear envelope. The NPCs allow passive diffusion of ions and small molecules, whereas nuclear proteins, RNAs, and ribonucleoproteins larger than ~9 nm in diameter are selectively and actively transported by a signal-mediated and energydependent mechanism. The signal for import is provided by a peptide sequence in the encoded protein known as the nuclear localization signal (NLS). The presence of several different NLSs and import factors suggests the existence of multiple pathways for such an import.
A number of nuclear transport receptors known as importins (karyopherins), transportins, and Ran-binding proteins recognize the NLS and mediate “docking” at the nuclear pore. Importin-a (karyopherin-a), the cytoplasmic receptor for NLS-bearing proteins, binds importin-b via a specific binding domain. Importin-b interacts with the importin-a bound to the NLS and acts as a carrier of the NLS/importin-a/b trimer. This trimeric complex docks to the cytoplasmic filaments of the NPC via importin-b. Subsequent passage of import substrates from the NPC into the nuclear interior requires the small GTPase, Ran, which plays a crucial role in both import/export pathways and determines the directionality of nuclear transport. Once in the nucleus, importin-b binds RanGTP and the import complex is disassembled and the substrate is retained in the nucleus. Ran is reported to shuttle between the nucleus and the cytoplasm and its recycling is essential for nuclear transport. In the cytoplasm, Ran is kept primarily in its GDP-bound form to facilitate import. On the other hand, in the nucleus, Ran is bound to GTP through RCC1, which facilitates export of proteins.
Malfunctioning of the nucleo-cytoplasmic transport is profoundly involved in a number of diseases. Defects in nuclear pore complex components have been implicated in several autoimmune disorders and cancers. At least 11 chromosomal rearrangements in acute leukemia involve nuclear pore protein (nucleoporin) genes. Leukemias associated with nucleoporin gene rearrangements have been reported to be more refractory to therapeutic intervention.
| | | | | | Inhibitors: Nuclear Import/Export |
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| InSolution™ Leptomycin A, Streptomyces sp. |
431051 |
| InSolution™ Leptomycin B, Streptomyces sp. |
431050 |
| InSolution™ Ratjadone A, Synthetic |
553590 |
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