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  • Review Article
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Nuclear transport and cancer: from mechanism to intervention

Nature Reviews Cancer volume 4, pages 106–117 (2004)Cite this article

Key Points

  • Nuclear-cytoplasmic transport of oncogenes and tumour suppressors is disrupted in cancer cells. Transport can be regulated by modification of the cargo, at the level of the transport machinery or at the level of the nuclear-pore complex (NPC). Modifying the nuclearcytoplasmic transport activity might block tumorigenesis.

  • Karyopherin-α and karyopherin-β transport cargoes that contain nuclear localization signals (NLSs) into the nucleus through the NPC. CRM1 is the transport receptor that exports nuclear export signal (NES)-containing proteins out of the nucleus.

  • The RanGTP/GDP gradient across the nuclear envelope promotes the direction of transport.

  • Hyper-active forms of AKT can lead to the mislocalization and therefore inactivation of proteins such as the FOXO transcription factors and p27 cell-cycle inhibitor.

  • Wild-type p53 is mislocalized to the cytoplasm in many cancers, possibly due, in part, to association with the cytoplasmic anchor protein PARC.

  • Stable, nuclear β-catenin is a hallmark of colon cancer cells. Experiments have implicated inefficient export by a mutant form of APC as a possible cause of nuclear β-catenin.

  • Altered expression of nuclear transport factors, such as karyopherins and nucleoporins, have been implicated in tumorigenesis.

  • Leptomycin B is a potent and specific covalent inhibitor of CRM1 and can sequester proteins in the nucleus.

  • Visual, high-throughput and high-content small-molecule screens for compounds that re-direct mislocalized proteins to the correct cellular compartment might reveal novel anticancer agents.

Abstract

Nuclear-cytoplasmic transport, which occurs through special structures called nuclear pores, is an important aspect of normal cell function, and defects in this process have been detected in many different types of cancer cells. These defects can occur in the signal-transduction pathways that regulate the transfer of factors such as p53 and β-catenin in and out of the nucleus, or in the general nuclear import and export machinery itself. In some cases, nuclear transport factors are overproduced, whereas in others, chromosomal translocations disrupt the structural proteins that make up the nuclear pore, leading to cell transformation. How does disruption of nuclear-cytoplasmic transport promote transformation, and is this process a viable therapeutic target?

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Figure 1: Schematic of nuclear-pore complex.
Figure 2: Nuclear-cytoplasmic transport of proteins.
Figure 3: Mislocalization of FOXO transcription factors and p27 by AKT phosphorylation.
Figure 4: Karyopherin-α reshuffling by CAS.

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Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Tweeny R. Kau & Pamela A. Silver

  2. Department of Cancer Biology, Dana–Farber Cancer Institute, Boston, 02115, Massachusetts, USA

    Tweeny R. Kau & Pamela A. Silver

  3. EMD Lexigen Research Center, Billerica, 01821, Massachusetts, USA

    Jeffrey C. Way

Authors
  1. Tweeny R. Kau
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  2. Jeffrey C. Way
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  3. Pamela A. Silver
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Correspondence to Pamela A. Silver.

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Related links

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DATABASES

Cancer.gov

acute myelogenous leukaemia

breast cancer

childhood acute lymphoblastic leukaemia

colorectal cancer

endometrial cancer

glioblastoma multiforme

Hodgkin's lymphoma

melanoma

neuroblastoma

oesophageal cancer

ovarian cancer

prostate cancer

renal-cell carcinoma

retinoblastoma

thyroid cancer

LocusLink

AKT

APC

β-catenin

CAS

CDK2

CK1

CRM1

CTNNB1

DYRK1A

FOXO1a

FOXO3a

FOXO4

GSK3

HOXA9

INI1

karyopherin-α

karyopherin-β

LEF1

MDM2

MEK1

NF-κB

NUP98

NUP214

p27

p53

p300

PAK1

PARC

PTEN

SGK

FURTHER INFORMATION

Advances in Cell Nucleus Research

Institute of Chemistry and Cell Biology and Initiative for Chemical Genetics

Silver lab web site

The cell nucleus webring

Glossary

NUCLEAR-PORE COMPLEX

An aqueous channel that is composed of proteins (called nucleoporins) in the nuclear envelope, through which macromolecules move between the nucleus and cytoplasm.

FORKHEAD TRANSCRIPTION-FACTOR SUPERFAMILY

A large superfamily of transcription factors, of which one family, FOXO, is phosphorylated and inhibited by AKT/PKB.

COWDEN'S DISEASE

Also known as multiple harmatoma syndrome. An autosomal-dominant condition that is marked by hereditary predisposition for developing cancers due to mutation of the PTEN gene.

LEPTOMYCIN B

A natural product that is isolated from Streptomyces and that inhibits CRM1 export activity by covalently binding to the Cys528 residue and preventing CRM1–substrate binding.

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Kau, T., Way, J. & Silver, P. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer 4, 106–117 (2004). https://doi.org/10.1038/nrc1274

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