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 stimulates the enzymatic activity of the Src protooncogene family protein tyrosine kinase LYN. LYN activation in irradiated cells is not triggered by DNA damage or a nuclear signal since gamma-rays effectively stimulated LYN kinase in enucleated B-cell precursors as well. LYN activation in irradiated cells was abrogated by presence of the OH* radical scavenger dimethylsulfoxide and exposure of intact or enucleated B-cell precursors to chemically generated OH* radicals instead of gamma-rays also triggered LYN kinase activation and enhanced tyrosine phosphorylation of multiple electrophoretically distinct protein substrates. Thus, OH* radicals appear to be both mandatory and sufficient for radiation-induced LYN kinase activation in irradiated B-cell precursors. We further present evidence which indicates that OH* radicals activate LYN by a novel mechanism which involves disruption of inactive LYN-LYN homodimers and monomerization of the LYN kinase after proteolytic degradation of a putative LYN-associated adapter protein through a cytoplasmic TPCK-sensitive chymotrypsin-like protease following its oxidation. LYN kinase plays a pivotal role in initiation of signal cascades that affect the proliferation, differentiation, and survival of B-cell precursors. Our results prompt the hypothesis that a growth regulatory balance might be altered in human B-cell precursors by radiation-induced stimulation of LYN kinase.
Xiao
J
J
Dept. of Therapeutic Radiology-Radiation Oncology, University of Minnesota Health Sciences Center, USA.
Biaglow
J E
JE
Chae-Park
H J
HJ
Jin
J
J
Tuel-Ahlgren
L
L
Myers
D E
DE
Burkhardt
A L
AL
Bolen
J B
JB
Uckun
F M
FM
D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000528:radiation effects*; D002460:Cell Line; D004789:Enzyme Activation; D005720:Gamma Rays; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D019000:Phosphotyrosine / Q000032:analysis; D011480:Protease Inhibitors / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism* / Q000528:radiation effects
D011480:Protease Inhibitors; D019000:Phosphotyrosine; D017665:Hydroxyl Radical; D014108:Tosylphenylalanyl Chloromethyl Ketone; D019061:src-Family Kinases; D017027:Protein Tyrosine Phosphatases