c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic. Role in carcinogenesis.
Environmental or occupational exposure to arsenic is associated with a greatly increased risk of skin, urinary bladder, and respiratory tract cancers in arseniasis-endemic areas throughout the world. Arsenic shares many properties of tumor promoters by affecting specific cell signal transduction pathways responsible for cell proliferation. The activation of the epidermal growth factor receptor (EGFR)-extracellular signal-regulated protein kinase (ERK) pathway is important in mediating gene expression related to regulation of cellular growth. In the current studies, we demonstrate that arsenic activates EGFR and ERK in a human uroepithelial cell line. The EGFR phosphorylation by arsenic is ligand-independent and does not involve the major autophosphorylation site Tyr(1173). c-Src activity is also induced by arsenic and is a prerequisite for the EGFR and ERK activation. Consistent with these in vitro observations, exposure of mice to arsenic in drinking water, which has been found previously to be associated with AP-1 activation and epithelial proliferation, induces EGFR and ERK activation in the urinary bladder. This response is also accompanied with an increase in c-Src levels interacting with EGFR. These findings represent a potential pathway for mediating arsenic-induced phenotypic changes in the uroepithelium.
Simeonova
Petia P
PP
TMBB, HELD, National Institute for Occupational Safety and Health, Centers for Disease Control, Morgantown, West Virginia 26505, USA. PSimeonova@cdc.gov
Wang
Shiyi
S
Hulderman
Tracy
T
Luster
Michael I
MI
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001151:Arsenic / Q000737:chemistry*; D001665:Binding Sites; D015153:Blotting, Western; D002273:Carcinogens; D002455:Cell Division; D002460:Cell Line; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000737:chemistry*; D005260:Female; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009369:Neoplasms / Q000139:chemically induced*; D010641:Phenotype; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000737:chemistry*; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry; D014551:Urinary Tract / Q000187:drug effects / Q000378:metabolism; D014565:Urogenital Neoplasms / Q000201:enzymology
D002273:Carcinogens; D008024:Ligands; D018808:Transcription Factor AP-1; D014443:Tyrosine; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D020928:Mitogen-Activated Protein Kinases; D001151:Arsenic