Coordinated regulation of radioadaptive response by protein kinase C and p38 mitogen-activated protein kinase

Eukaryotic cells are known to have an inducible or adaptive response that e nhances radioresistance after a low priming dose of radiation. This radioad aptive response seems to present a novel cellular defense mechanism. Howeve r, its molecular processing and signaling mechanisms are largely unknown. H ere, we studied the role of protein kinase C (PKC) and mitogen-activated pr otein kinase (MAPK) in the expression of radioadaptive response in cultured mouse cells. Protein immunoblot analysis using isoform-specific antibodies showed an immediate activation of PKC-alpha upon X-irradiation as indicate d by a translocation from cytosol to membrane. A low priming dose caused a prolonged translocation, while a nonadaptive high dose dramatically downreg ulated the total PKC level. Low-dose X-rays also activated the p38 MAPK. Th e activation of p38 MAPK and resistance to chromosome aberration formation were blocked by SB203580, an inhibitor of p38 MAPK, and Calphostin C, an in hibitor of PKC. Furthermore, it was demonstrated that p38 MAPK was physical ly associated with delta 1 isoform of phospholipase C (PLC-delta 1), which hydrolyzed phosphatidylinositol bisphosphate into diacylglycerol, an activa tor of PKC, and that SB203580 also blocked the activation of PKC-alpha. The se results indicate the presence of a novel mechanism for coordinated regul ation of adaptive response to low-dose Xrays by a nexus of PKC-alpha/p38 MA PK/PL-delta 1 circuitry feedback signaling pathway with its breakage operat ed by downregulation of labile PKC-alpha at high doses or excess stimuli. ( C) 1999 Academic Press.