The 14-3-3 cancer connection

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.