DNA damage-induced 14-3-3σ Signaling

The 14-3-3 proteins comprise a large family of highly conserved, small, acidic polypeptides that are found in all eukaryotic species and play important roles in a wide range of cellular processes including signal transduction, apoptosis, cell cycle progression and checkpoint activation. In humans, seven different genes encode the highly conserved 14-3-3 isotypes (α, β, γ, δ, ε, η, σ, τ, and ζ). The 14-3-3 proteins regulate numerous cellular signaling circuits that are implicated in cancer development. They bind to protein ligands following their serine/threonine phosphorylation at a defined motif and regulate their activities by different mechanisms. These include inter- and intra-compartmental sequestration, activation/inactivation of enzymatic activity and promotion/inhibition of protein interactions.14-3-3 proteins play a critical role in DNA damage-induced checkpoints by controlling the biological activity of several key cell cycle checkpoint proteins through binding to phosphorylated serine residues. In normal cells, DNA damage leads to activation of cell cycle checkpoints and arrest in the G1 and G2 phases of the cell cycle. Of all the 14-3-3 family members, 14-3-3σ has been most directly linked to cancer. It functions as a tumor suppressor by inhibiting cell cycle progression and by causing cells to leave the stem-cell phenotype and undergo differentiation. 14-3-3σ is induced by DNA damage and is required for a stable G2 cell cycle arrest in epithelial cells. DNA damage generates a 14-3-3-binding motif in the carboxyl terminus of the tumor suppressor protein p53. The subsequent association of p53 with 14-3-3 proteins leads to an increase in its DNA-binding activity, which has a direct effect on cell cycle progression as it affects the localization of CDK2 and CDC2. 14-3-3σ normally sequesters cyclin B, cyclin E and CDC2 in the cytoplasm, keeping CDC2-cyclin B and CDK2-cyclin E complexes from entering the nucleus and initiating mitosis. Loss of the ability to bind 14-3-3 proteins leads to a strongly reduced ability of p53 to induce genes that mediate cell cycle arrest after DNA damage.In addition to regulating kinases after activation of DNA-damage checkpoints, 14-3-3 proteins regulate the activity of transcription factors that induce negative regulators of the cell cycle machinery. 14-3-3σ is also induced by BRCA1 and is thereby part of the concerted activation of regulators that is mediated through BRCA1 after induction of DNA damage induced kinases ATM/ATR and the checkpoint proteins Rad1, Rad9 and Hus1 which act as DNA-damage detectors. 14-3-3σ expression is restricted to epithelial cells and increases during epithelial differentiation. 14-3-3σ is silenced by CpG methylation in a large proportion of carcinomas, which can be used for diagnosis. Inactivation of 14-3-3σ leads to immortalization of primary keratinocytes and prevents exit from the stem cell phenotype. Loss of 14-3-3σ expression sensitizes tumor cells to treatment with conventional cytostatic drugs. Modulation of 14-3-3σ activities might therefore be an attractive therapeutic approach for the treatment of lung cancer, especially in combination with radiotherapy.