Okadaic acid induces cellular hypertrophy in AKR-2B fibroblasts: involvement of the p70S6 kinase in the onset of protein and rRNA synthesis

At low concentrations (50 nM), okadaic acid (OA), an inhibitor of phosphatases I and 2A, inhibits plateletderived growth factor-induced cell proliferation in late G1 (A. Simm et aL, Exp. Cell Res., 210 160-165, 1994). This Inhibition is caused by the Interference of OA in the induction and activation of the cell division protein kinases cdkl and cdk2. OA alone has no effect on cell number, but induces a pronounced increase in cell size. The OA-induced hypertrophy can be dMded into two phases. The first phase is characterized by a swelling of the cells. This increase in cellular volume is not accompanied by a change in the level of cellular macromolecules, i.e., protein and RNA. Inhibitor studies indicated a possible role of the Na�’iH� antiporter and Cl channels in this process. In the second phase, an increase in the cellular protein and RNA content was observed along with a minor change in cell volume. To delineate a possible signaling pathway, the involvement of numerous protein kinases was analyzed. Low concentrations of OA lead to pronounced and sustained activation of the p7O� kinase. There was little or no effect on various other kinases that can be activated by extracellular signals,