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(Journal of Leukocyte Biology. 2002;71:487-494.)
© 2002 by Society for Leukocyte Biology

Beryllium fluoride-induced cell proliferation: a process requiring P21^ras-dependent activated signal transduction and NF-B-dependent gene regulation

Department of Pathology, Duke University Medical Center, Durham, North Carolina

Correspondence: Salvatore V. Pizzo, M.D., Ph.D., Professor and Chairman of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. E-mail: Pizzo001{at}mc.duke.edu

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), BeF₂ caused an approximate twofold increase in [³H]thymidine uptake and cell number, but above 5 nM, it showed cytotoxic effects. BeF₂ increased cellular inositol (1,4,5)trisphosphate (IP₃) and [Ca²⁺]_i about twofold. The rise in [Ca²⁺]_i occurred consequent to release from IP₃-sensitive Ca²⁺ 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 BeF₂-exposed macrophages. The levels of NF-B and CREB transcription factors and the proto-oncogenes c-fos and c-myc were also elevated significantly. Intracellular Ca²⁺ chelation blocked the effect of BeF₂. We conclude that BeF₂ at low concentration exerts its mitogenic effects in peritoneal macrophages by elevating [Ca²⁺]_i, which triggers the activation of p21^ras-dependent MAPK signaling cascades.

Key Words: mitogenesis • MAPK regulation • AlF_n • CREB

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