ROLE OF HYDROXYL RADICALS IN RADIATION-INDUCED ACTIVATION OF LYN TYROSINE KINASE IN HUMAN B-CELL PRECURSORS

Here we show that exposure of human B-cell precursors to gamma-rays st imulates the enzymatic activity of the Src protooncogene family protei n tyrosine kinase LYN. LYN activation in irradiated cells is not trigg ered by DNA damage or a nuclear signal since gamma-rays effectively st imulated LYN kinase in enucleated B-cell precursors as well. LYN activ ation in irradiated cells was abrogated by presence of the OH radical scavenger dimethylsulfoxide and exposure of intact or enucleated B-ce ll precursors to chemically generated OH radicals instead of gamma-ra ys also triggered LYN kinase activation and enhanced tyrosine phosphor ylation of multiple electrophoretically distinct protein substrates. T hus, OH radicals appear to be both mandatory and sufficient for radia tion-induced LYN kinase activation in irradiated B-cell precursors. We further present evidence which indicates that OH radicals activate L YN by a novel mechanism which involves disruption of inactive LYN-LYN homodimers and monomerization of the LYN kinase after proteolytic degr adation of a putative LYN-associated adapter protein through a cytopla smic TPCK-sensitive chymotrypsin-like protease following its oxidation . LYN kinase plays a pivotal role in initiation of signal cascades tha t affect the proliferation, differentiation, and survival of B-cell pr ecursors. Our results prompt re hypothesis that a growth regulatory ba lance might be altered in human B-cell precursors by radiation-induced stimulation of LYN kinase.