Beryllium fluoride-induced cell proliferation: a process requiring P21(ras)-dependent activated signal transduction and NF-kappaB-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-kappaB 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.
Misra
Uma Kant
UK
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
Gawdi
Govind
G
Pizzo
Salvatore Vincent
SV
D000818:Animals; D001608:Beryllium / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005459:Fluorides / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
D016328:NF-kappa B; C035982:beryllium fluoride; D016283:Proto-Oncogene Proteins p21(ras); D001608:Beryllium; D005459:Fluorides