Selective activation of Src family kinases and JNK by low levels of chromium(VI).
Inhaled hexavalent chromium (Cr(VI)) promotes pulmonary disease and lung cancer through poorly defined mechanisms. These mechanisms were studied in A549 lung epithelial cells to investigate the hypothesis that nontoxic Cr(VI) exposures selectively activate cell signaling that shifts the balance of gene transcription. These studies demonstrated that nontoxic doses of Cr(VI) (10 microM) increased reactive oxygen species and selectively activated c-Jun N-terminal kinase (JNK), relative to ERK or p38 MAP kinase. In contrast, only toxic, nonselective levels of exogenous oxidants stimulated JNK. However, JNK activation in response to Cr(VI) and exogenous H(2)O(2) (1 mM) shared requirements for intracellular thiol oxidation, activation of Src family kinases, and p130(cas) (Cas). Cr(VI) did not mimic H(2)O(2)-mediated stimulation of JNK in fibroblasts containing only Src and did not activate Src or Yes in A549 cells. Instead, Fyn and Lck were activated in A549 cells, indicating activation of specific Src family kinases in response to Cr(VI). Finally, Cr(VI) was demonstrated to directly activate purified Fyn in vitro and the majority of this activation did not require oxidant generation. These data suggest that nontoxic levels of Cr(VI), which can shift patterns of gene transcription, are selective in their activation of cell signaling and that Cr(VI) can directly activate Src family kinases independently of reactive oxygen species generation.
O'Hara
Kimberley A
KA
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755-3835, USA.
Klei
Linda R
LR
Barchowsky
Aaron
A
D002478:Cells, Cultured; D002857:Chromium / Q000633:toxicity*; D050719:Crk-Associated Substrate Protein; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D009363:Neoplasm Proteins; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D011506:Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000096:biosynthesis*
C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011506:Proteins; D017382:Reactive Oxygen Species; D050717:Retinoblastoma-Like Protein p130; D002857:Chromium; C074702:chromium hexavalent ion; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; C092830:FRK protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases