Abstract
Here, we present evidence that exposure of DT40 lymphoma B cells to low energy electromagnetic field (EMF) results in a tyrosine kinase-dependent activation of phospholipase Cgamma2 (PLC-gamma2) leading to increased inositol phospholipid turnover. B cells rendered PLC-gamma2-deficient by targeted disruption of the PLC-gamma2 gene as well as PLC-gamma2-deficient cells reconstituted with Src homology domain 2 (SH2) domain mutant PLC-gamma2 did not show any increase in inositol-1,4,5-trisphosphate levels after EMF exposure, providing direct evidence that PLC-gamma2 is responsible for EMF-induced stimulation of inositol phospholipid turnover, and its SH2 domains are essential for this function. B cells rendered SYK-deficient by targeted disruption of the syk gene did not show PLC-gamma2 activation in response to EMF exposure. The C-terminal SH2 domain of SYK kinase is essential for its ability to activate PLC-gamma2. SYK-deficient cells reconstituted with a C-terminal SH2 domain mutant syk gene failed to elicit increased inositol phospholipid turnover after EMF exposure, whereas SYK-deficient cells reconstituted with an N-terminal SH2 domain mutant syk gene showed a normal EMF response. LYN kinase is essential for the initiation of this biochemical signaling cascade. Lymphoma B cells rendered LYN-deficient through targeted disruption of the lyn gene did not elicit enhanced inositol phospholipid turnover after EMF exposure. Introduction of the wild-type (but not a kinase domain mutant) mouse fyn gene into LYN-deficient B cells restored their EMF responsiveness. B cells reconstituted with a SH2 domain mutant fyn gene showed a normal EMF response, whereas no increase in inositol phospholipid turnover in response to EMF was noticed in LYN-deficient cells reconstituted with a SH3 domain mutant fyn gene. Taken together, these results indicate that EMF-induced PLC-gamma2 activation is mediated by LYN-regulated stimulation of SYK, which acts downstream of LYN kinase and upstream of PLC-gamma2.
Highlights
§ Submitted to fulfill in part the requirements for a doctorate of philosophy at the University of Minnesota Graduate School, Minneapolis, MN 55417
B cells rendered phospholipase C␥2 (PLC-␥2)-deficient by targeted disruption of the PLC-␥2 gene as well as PLC-␥2-deficient cells reconstituted with Src homology domain 2 (SH2) domain mutant PLC-␥2 did not show any increase in inositol-1,4,5-trisphosphate levels after electromagnetic field (EMF) exposure, providing direct evidence that PLC-␥2 is responsible for EMF-induced stimulation of inositol phospholipid turnover, and its SH2 domains are essential for this function
Activation of PLC-␥2 in DT40 Lymphoma B Cells Exposed to Low Energy EMF—The catalytic activity of PLC-␥2 is regulated through tyrosine phosphorylation by receptor- and nonreceptor-type protein-tyrosine kinase (PTK), and biochemical signals that trigger tyrosine-specific protein phosphorylation have been shown to precede the activation of PLC-␥2 and stimulation of inositol phospholipid turnover in many experimental systems (10, 12– 17, 26)
Summary
§ Submitted to fulfill in part the requirements for a doctorate of philosophy at the University of Minnesota Graduate School, Minneapolis, MN 55417. We present evidence that exposure of DT40 lymphoma B cells to low energy electromagnetic field (EMF) results in a tyrosine kinase-dependent activation of phospholipase C␥2 (PLC-␥2) leading to increased inositol phospholipid turnover.
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