DNA Damage Induced 14-3-3Sigma Signaling
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DNA Damage Induced 14-3-3Sigma Signaling

The 14-3-3 proteins comprise a large family of highly conserved, small, acidic polypeptides of 28-33 kDa 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 (Ref.1). In humans, seven different genes encode the highly conserved 14-3-3 isotypes (Alpha, Beta, Gamma, Delta, Epsilon, Eta, Sigma, Tau, and Zeta, with Alpha and Delta being phosphorylated forms of Beta and Zeta). 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 a number of different mechanisms. These include inter- and intracompartmental 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. This requires inactivation of the cell cycle regulator CDC25C that dephosphorylates and activates the cyclin-dependent kinase CDC2 to trigger entry into mitosis (Ref.2). Phosphorylation of CDC25C on Ser216 creates a binding motif for 14-3-3, and this interaction combined with a strong 14-3-3 nuclear export signal promotes export of CDC25C from the nucleus and suppression of its biological activities (Ref.3). Of all the 14-3-3 genes, 14-3-3-Sigma 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 compartment and undergo differentiation. 14-3-3-Sigma is induced by DNA damage and is required for a stable G2 cell-cycle arrest in epithelial cells. After DNA damage, dephosphorylation of Ser376 generates a 14-3-3 binding motif in the carboxyl terminus of the tumor suppressor protein p53 (Ref.4). 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. 14-3-3-Sigma normally sequesters Cyclin B , Cyclin E and CDC2 in the cytoplasm, keeping CDC2-Cyclin B and CDK2-Cyclin E from entering the nucleus and initiating mitosis. Similarly, phosphorylation of CDC25 on Ser126 by Chk1 leads to an interaction with 14-3-3 and export from the nucleus, which prevents dephosphorylation and activation of CDC2 (Ref.5). 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 and phosphatases 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. 14-3-3-Sigma expression is also induced by the BRCA1 (Breast Cancer Susceptibility Protein-1) tumor-suppressor gene product, and is thereby part of the concerted activation of G2-M regulators that is mediated through BRCA1 after induction of DNA damage induced kinases ATM (Ataxia Telangiectasia-Mutated)/ATR (ATM/Rad3-related) and the "checkpoint Rad" proteins Rad1, Rad9, Rad17 and Hus1, which act as DNA-damage detectors (Ref.6).

14-3-3-Sigma expression is restricted to epithelial cells and increases during epithelial differentiation. 14-3-3-Sigma is silenced by CpG methylation in a large proportion of carcinomas, which can be used for diagnosis. Inactivation of 14-3-3-Sigma leads to immortalization of primary keratinocytes and prevents exit from the stem-cell compartment, indicating that this gene has suppressive-suppressive properties. Loss of 14-3-3-Sigma expression sensitizes tumor cells to treatment with conventional cytostatic drugs. Modulation of 14-3-3-Sigma activities might therefore be an attractive therapeutic approach for the treatment of lung cancer, especially together with radiotherapy.