ReviewNuclear transport as a target for cell growth
Section snippets
Nuclear transport of proteins
One of the hallmarks of eukaryotic cells is the containment of DNA in the cell nucleus, where transcription and replication are separated from protein synthesis in the cytoplasm. Transport of molecules between the cytoplasm and nucleus occurs across the nuclear envelope through the nuclear pore complex (NPC), a large protein structure of ∼125 megadaltons (MDa) that enables the passage of a variety of complexes, up to 120 kDa, the size of the large ribosomal subunit [1]. In principle, molecules
Nuclear export inhibitor leptomycin B as a cancer therapeutic
Isolated from a Streptomyces strain, leptomycin B (LMB) has, until recently, been the only known small-molecule inhibitor of nuclear transport. Leptomycin B is an unsaturated branched-chain fatty acid (Fig. 2) and has been shown to have antifungal, antibacterial and anti-tumor activity 6., 7., 8.. Furthermore, LMB causes cell-cycle arrest at stages G1 and G2 of the cell cycle in yeast and mammalian cells [9]. Leptomycin B was first implicated as an inhibitor of nuclear export in a screen for
Targeting nuclear localization of key transcription factors in disease
Several well-characterized transcription factors have been implicated in tumorigenesis. As transcription occurs in the cell nucleus, the activity of these factors can be regulated by their subcellular localization 23., 24.. Thus, identifying small molecules that affect the localization of transcription factors can be an effective target for the control of unwanted cell growth.
Moving proteins with peptide aptamers
In contrast to inhibiting the endogenous signaling pathways of a cell to re-localize effectors of cell death or cell growth, peptide aptamers enable the active targeting of effectors to the nucleus or cytoplasm. Analogous to monoclonal antibodies, peptide aptamers are small proteins that contain a structurally constrained variable region of ∼20 amino acids, expressed as part of an inert scaffold such as thioredoxin or green fluorescent protein [70]. Peptide aptamers that have been created
Future implications
Using small molecules or peptide aptamers to alter the cellular localization of a protein can reveal much about its cell biology. In addition, the spatial localization of a target offers another dimension or variable that researchers could exploit to control cancer cell growth. This review has described several methods for targeting nuclear transport, and these methods can range widely, from inhibiting the general protein transport machinery, to using small-molecule protein or lipid-kinase
Acknowledgements
We would like to thank Charles Cho, Paul Ko Ferrigno and Jason Casolari for their helpful comments, and Eric Smith for providing the artwork.
References (74)
Nucleocytoplasmic transport: the last 200 nanometers
Cell
(1998)- et al.
Diverse nuclear transport pathways regulate cell proliferation and oncogenesis
Biochim. Biophys. Acta
(2000) Effects of leptomycin B on the cell cycle of fibroblasts and fission yeast cells
Exp. Cell Res.
(1990)Leptomycin B is an inhibitor of nuclear export: inhibition of nucleo-cytoplasmic translocation of the human immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent Mrna
Chem. Biol.
(1997)Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression
J. Biol. Chem.
(1994)CRM1 is an export receptor for leucine-rich nuclear export signals
Cell
(1997)Exportin 1 (Crm1p) is an essential nuclear export factor
Cell
(1997)Leptomycin B inhibition of signal mediated nuclear export by direct binding to CRM1
Exp. Cell Res.
(1998)Accumulating active p53 in the nucleus by inhibition of nuclear export: a novel strategy to promote the p53 tumor suppressor function
Exp. Cell Res.
(1999)- et al.
Nuclear transport and transcription
Curr. Opin. Cell Biol.
(2000)