Thiol modification and cell signalling in chemical toxicity.
Exposure of cells to thiol oxidizing agents can result in the modification of key proteins involved in cell signalling. Such changes have been shown to affect agonist-stimulated phosphoinositide metabolism, activation of protein kinases and intracellular Ca2+ signals, which result in abnormalities in cell metabolisms and growth. Here, we show that moderate levels of oxidants potentiate growth signals and either enhance cell proliferation or facilitate cell differentiation, whereas inhibition of growth signals by higher oxidant concentrations can block cell proliferation and activate programmed cell death (PCD). Finally, a general alteration of multiple signalling pathways associated with increased catabolic reactions results in cell death by necrosis. Our data suggest that oxidant interaction with cell signalling systems may exert opposite effects, depending on the dose, and that oxidative reactions may either mimic growth factor stimulation and stimulate cell proliferation or inhibit growth signals and activate PCD, in the same cell systems.
Nicotera
P
P
Department of Toxicology, Karolinska Institutet Stockholm, Sweden.
Dypbukt
J M
JM
Rossi
A D
AD
Manzo
L
L
Orrenius
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008627:Mercuric Chloride / Q000633:toxicity; D009285:Naphthoquinones / Q000494:pharmacology; D016877:Oxidants / Q000633:toxicity*; D016716:PC12 Cells; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D009285:Naphthoquinones; D016877:Oxidants; D013438:Sulfhydryl Compounds; D008627:Mercuric Chloride; C063002:2,3-dimethoxy-1,4-naphthoquinone; D011493:Protein Kinase C; D002118:Calcium