Beryllium fluoride‐induced cell proliferation: a process requiring P21 ras ‐dependent activated signal transduction and NF‐κB‐dependent gene regulation

We studied the effect of beryllium fluoride on murine peritoneal macrophages and determined its effects on signal transduction and genetic regulation. At low concentration (1–5 nM), BeF 2 caused an approximate twofold increase in [ 3 H]thymidine uptake and cell number, but above 5 nM, it showed cytotoxic effects. BeF 2 increased cellular inositol (1,4,5)trisphosphate (IP 3 ) and [Ca 2 + ] i about twofold. The rise in [Ca 2 + ] i occurred consequent to release from IP 3 ‐sensitive Ca 2 + stores and from influx, mainly via L‐type channels. A significant increase in the levels of MEK1, ERK1, p38 MAPK, and JNK phosphorylation was observed in BeF 2 ‐exposed macrophages. The levels of NF‐κB and CREB transcription factors and the proto‐oncogenes c‐fos and c‐myc were also elevated significantly. Intracellular Ca 2 + chelation blocked the effect of BeF 2 . We conclude that BeF 2 at low concentration exerts its mitogenic effects in peritoneal macrophages by elevating [Ca 2 + ] i , which triggers the activation of p21 ras ‐dependent MAPK signaling cascades.