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The 14-3-3 cancer connection

Key Points

  • Processes that are relevant to cancer biology and that are regulated by 14-3-3 protein interactions include cell-cycle progression, apoptosis and mitogenic signalling.

  • 14-3-3 proteins bind to protein ligands that have been phosphorylated on serine/threonine residues in a consensus binding motif. There are, however, a few proteins that associate with 14-3-3s independently of this motif.

  • 14-3-3 proteins regulate other proteins by cytoplasmic sequestration, occupation of interaction domains and export or import sequences, prevention of degradation, activation/repression of enzymatic activity and transactivation, and facilitation of protein modifications. These effects are caused by 14-3-3-mediated conformational changes or steric hindrance.

  • 14-3-3 proteins form dimers that provide two binding sites for phosphoserine motifs in ligand proteins. They can therefore function as adaptor proteins, bringing two proteins that would not otherwise associate into close proximity. In addition, ligands with two 14-3-3-binding motifs might be bound with higher affinity by one 14-3-3 dimer.

  • In humans, seven expressed 14-3-3 isoforms have been identified, one of which — 14-3-3σ — is induced by DNA damage and is required for a stable G2 cell-cycle arrest in epithelial cells. The 14-3-3σ gene is directly regulated by p53; furthermore, 14-3-3σ is silenced by CpG methylation in a large proportion of carcinomas, which could be used for diagnosis.

  • 14-3-3σ expression is restricted to epithelial cells and increases during epithelial differentiation. Inactivation of 14-3-3σ leads to immortalization of primary keratinocytes and prevents exit from the stem-cell compartment, indicating that this gene has tumour-suppressive properties.

  • Loss of 14-3-3σ expression sensitizes tumour cells to treatment with conventional cytostatic drugs. Modulation of 14-3-3σ activity might therefore be an attractive therapeutic approach.

Abstract

14-3-3 proteins regulate many cellular processes that are important in cancer biology, such as apoptosis and cell-cycle checkpoints. There are seven human 14-3-3 genes and one of these, 14-3-3σ, has been directly implicated in the aetiology of human cancer. Loss of 14-3-3σ expression sensitizes cancer cells to conventional anticancer agents, so its inhibition could be exploited for therapeutic purposes. Interference with 14-3-3 function as a therapeutic approach is being evaluated at present and, in the case of UCN-01, is under clinical investigation.

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Figure 1: 14-3-3 proteins: 'molecular anvils' that mediate conformational changes or steric hindrance, with functional consequences.
Figure 2: The diverse roles of 14-3-3 proteins in cell-cycle regulation.
Figure 3: DNA damage induces 14-3-3 functions upstream and downstream of p53.
Figure 4: Function of 14-3-3 proteins in the regulation of BAD activity and apoptosis.
Figure 5: 14-3-3σ regulation in normal and cancer cells.
Figure 6: Therapeutic interference with 14-3-3 functions.

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Acknowledgements

The author thanks A. Menssen, F. Melchior, L. Hengst and A. Benzinger for helpful comments. Work in the author's laboratory is supported by the Max-Planck-Society, Deutsche Krebshilfe, Thyssen-Foundation, Rudolf-Bartling-Foundation, and Studienstiftung des Deutschen Volkes.

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DATABASES

LocusLink

14-3-3 family

AKT

ATM

BAD

BCL2

BCL-XL

BRCA1

CDC2

CDC25 family

CHK1

cyclin B1

EFP

p53

p63

p73

PKA

PPA2

PTEN

RAF1

WEE1

FURTHER INFORMATION

Heiko Hermeking's laboratory

Scansite

Glossary

SAGE

(Serial analysis of gene expression). Quantification of global gene-expression patterns based on large-scale sequencing of short sequence tags derived from the 3′ ends of messenger RNAs; this technique has been used extensively to characterize cancer-cell transcriptomes.

MITOTIC CATASTROPHE

Cells that enter mitosis prematurely in the presence of DNA damage undergo an aberrant mitosis that results in cell death.

MAINTENANCE METHYLASE DNMT1

Required for maintenance of the inherited methylation pattern; this enzyme uses hemimethylated DNA as a substrate after DNA replication.

DE NOVO METHYLASE DNMT3B

Required for the de novo methylation that occurs during early development and gametogenesis.

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Hermeking, H. The 14-3-3 cancer connection. Nat Rev Cancer 3, 931–943 (2003). https://doi.org/10.1038/nrc1230

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