14-3-3 and Cell Cycle Regulation
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14-3-3 and Cell Cycle Regulation

14-3-3 proteins are a family of acidic regulatory molecules found in all eukaryotes. 14-3-3 proteins function as molecular scaffolds by modulating the conformation of their binding partners. While lower eukaryotes, e.g. yeast, contain only two 14-3-3 genes, higher eukaryotes possess up to 15 14-3-3 genes. For example, in mammals seven isoforms (beta, epsilom, eta, gamma, tau, zeta and sigma) have been identified to date. 14-3-3 proteins are involved in many processes, including cell cycle regulation, metabolism control, apoptosis, and control of gene transcription. The role of 14-3-3 proteins during cell cycle progression include regulating the onset and timing of mitosis in cycling cells, maintaining a stable G1-arrest in non-cycling cells and necessary for the S-phase checkpoint after DNA-damage by UV-B (Ref.1 and 2).

14-3-3 proteins regulate the cell cycle and prevent apoptosis by controlling the nuclear and cytoplasmic distribution of signaling molecules with which they interact. 14-3-3 proteins have crucial functions during undisturbed cell divisions and several mechanisms involving 14-3-3 ligand association ensure that mitosis is not prematurely activated before the completion of DNA replication in interphase. The tyrosine kinase Wee1 is activated by phosphorylation during interphase, this involves association with 14-3-3 proteins after phosphorylation of Ser642. Active Wee1 inhibits CDC2 by Tyr15 phosphorylation. In parallel, CDC25C the main inducer of CDC2 is kept in an inactive state by phosphorylation at Ser216 by TAK1 (TGF-Beta-Activating Kinase-1 or other kinase), which results in cytoplasmic sequestration by 14-3-3 proteins. Once mitosis is activated, cytoplasmic sequestration of CDC25C is inhibited by a CDC2-mediated phosphorylation of CDC25C at Ser214, which prevents phosphorylation at Ser216 and, thereby, 14-3-3 association of CDC25C. Similar mechanisms apply to CDC25B. Thus CDC25C and CDC25B proteins are dual-specificity phosphatases that remove inhibitory phosphate groups from Thr14 and Tyr15, and thereby activate the cyclin-dependent kinase CDC2 (Ref.2). DNA damage induces phosphorylation and 14-3-3 association of the serine/threonine kinase Chk1, which activates the same 14-3-3-dependent pathways that are used during interphase to inhibit the initiation of mitosis. In response to Ultraviolet light (UV), the p38 MAPK (Mitogen-Activated Protein Kinase) becomes active and mediates phosphorylation of CDC25B at Ser309, which results in association with 14-3-3 and relocalization of CDC25B to the cytoplasm. Once a cell has entered mitosis, inhibition of CDC25C and also CDC25B is prevented by CDC2-mediated phosphorylation in a positive-feedback loop. This imposes a rapid, but transient, cell-cycle arrest. 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 (Ref.3, 4 and 5).

14-3-3 proteins are abundantly expressed in the brain and have been detected in the cerebrospinal fluid of patients with different neurological disorders. By their interaction with more than 100 binding partners, 14-3-3 proteins modulate the action of proteins that are involved in regulation of cell cycle arrest in response to DNA damage, cell cycle timing, intracellular trafficking, regulation of ion channels, and intracellular signaling in response to stress, mating pheromone in yeast, photoreceptor development and learning in Drosophila, cellular response to stress and survival factors in mammals, and various organisms (Ref.6 and 7). 14-3-3 proteins continue to generate intense interest because of their roles in signal transduction pathways that control cell cycle checkpoints, apoptosis and programs of gene expression. Despite this plethora of known binding proteins, in many cases the function of 14-3-3 in these interactions has remained obscure.