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The microtubular cytoskeleton and the initiation of DNA synthesis
Abstract:
Depending on cell type and mode of growth stimulation, an intact cytoplasmic microtubule system may either support or suppress passage through the prereplicative G1 phase (growth and maturation) and entrance into the S phase (DNA synthesis) of the cell cycle. In peripheral blood lymphocytes exposed to mitogenic lectins, colchicine and other antimicrotubular drugs inhibit blast transformation and initiation of DNA synthesis. The inhibitory effect is not due to decreased cellular binding of lectin or lack of generation of a stimulatory signal. Rather, it can be explained by an inability of the cells to pass through the G1 phase at a normal rate in the absence of cytoplasmic microtubules. The formation of new organelles and the growth in cell size that occur during this phase is markedly delayed by the drugs. For example, the Golgi complex, an organelle system that participates in membrane biogenesis and other basic cellular functions, is reduced in size and structurally disorganized. In cells with a shorter prereplicative phase, such as fibroblasts and smooth muscle cells, antimicrotubular drugs inhibit DNA synthesis in growth-arrested cultures exposed to optimal concentrations of serum, thrombin or platelet-derived growth factor (PDGF). On the other hand, antimicrotubular drugs stimulate DNA replication in serum-free cultures and enhance the stimulatory effect of insulin, epidermal growth factor (EGF), fibroblast growth factor (FGF), and prostaglandin F2 alpha on entrance into S phase. Moreover, stabilization of cytoplasmic microtubules with taxol has been found to block microtubule disassembly and initiation of DNA synthesis by colchicine and to inhibit thrombin- and EGF-stimulated DNA synthesis under serum-free conditions. These findings suggest that partial microtubule disassembly is an inherent step in the reactions that precede DNA replication and mitosis. However, the cell biological and molecular details of these reactions and the exact role of microtubules remain enigmatic.