Nucleo-cytoplasmic transport of proteins as a target for therapeutic drugs.
Recruitment of cytoplasmic signaling proteins into the nucleus is an essential step in the activation of gene expression in response to an extracellular signal. Nucleo-cytoplasmic transport of macromolecules is mediated by the transport receptors of an importin beta family. Post-translational modifications and masking/unmasking of specific signal sequences responsible for nuclear import and export are important for the coordinated control of the nucleo-cytoplasmic transport. Malfunctioning of the nucleo-cytoplasmic transport is profoundly involved in a number of diseases including cancer. Leptomycin B (LMB) is a Streptomyces metabolite that causes specific inhibition of the cell cycle of fission yeast and mammalian cells. The target molecule of LMB has been shown by genetic and biochemical analyses to be CRM1, a highly conserved protein in eukaryotes. CRM1 was shown to be a member of the importin beta family and a receptor for the nuclear export signal (NES) of proteins in both yeast and mammalian cells. LMB binds directly to CRM1, which results in dissociation of the NES from the nuclear export machinery containing CRM1. Thus, LMB serves as a potent tool for understanding the molecular mechanisms of nucleo-cytoplasmic transport of proteins and a potential therapeutic drug for diseases caused by mislocalization of regulatory proteins.
Yashiroda Y, Yoshida M