Elsevier

Drug Discovery Today

Volume 8, Issue 2, 15 January 2003, Pages 78-85
Drug Discovery Today

Review
Nuclear transport as a target for cell growth

https://doi.org/10.1016/S1359-6446(02)02562-XGet rights and content

Abstract

The function of many key proteins and transcription factors involved in cell growth can be regulated by their cellular localization. Such proteins include the tumor suppressor p53 and the nuclear factor κB. Although the idea of trapping such proteins in either the nucleus or cytoplasm has been introduced as a potential therapeutic target, only two nuclear transport inhibitors have been reported. Here, we explore the roles of small-molecule inhibitors that cause target proteins to sequester in either the nucleus or cytoplasm. Methods of artificially targeting proteins to the nucleus or cytoplasm using peptide aptamer technology are also discussed.

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.

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