TY - JOUR
T1 - Low concentrations of inorganic mercury inhibit Ras activation during T cell receptor-mediated signal transduction
AU - Mattingly, Raymond R.
AU - Felczak, Aimee
AU - Chen, Chien Chung
AU - McCabe, Michael J.
AU - Rosenspire, Allen J.
PY - 2001/11/1
Y1 - 2001/11/1
N2 - Mercury is widespread in the environment and consequently there are large populations that are currently exposed to low levels of mercury as a result of ubiquitous environmental factors. Whether these environmental levels of mercury are harmful is a matter of current debate, with epidemiological and animal studies suggesting detrimental effects on the immune and nervous systems. However, specific cellular effects of low concentrations of mercury have been hard to characterize. We now demonstrate that subtoxic concentrations of HgCl2 can potently (maximal at 1 μM) increase Ras. GTP levels in Jurkat, a human T cell line. Remarkably, this activation of Ras occurs without a concomitant increase in MAP kinase activation, suggesting that mercury may direct Ras into a nonproductive state. In addition to its direct effect on Ras, concentrations of HgCl2 as low as 0.6 μM inhibited the ability of the T cell receptor to activate Ras and MAP kinase. The inhibitory effect of mercury is selective, as activation of MAP kinase by phorbol diesters remain intact. Since the Ras/MAP kinase pathway is both highly conserved and central to signal transduction processes mediated by a myriad of diverse membrane receptor systems in a variety of cell types, these results suggest a mechanism for adverse health effects resulting from exposure to low levels of mercury. They also support a model for regulation of the Ras/MAP kinase pathway, whereby partial but unproductive activation of Ras can diminish signaling from cell surface receptors.
AB - Mercury is widespread in the environment and consequently there are large populations that are currently exposed to low levels of mercury as a result of ubiquitous environmental factors. Whether these environmental levels of mercury are harmful is a matter of current debate, with epidemiological and animal studies suggesting detrimental effects on the immune and nervous systems. However, specific cellular effects of low concentrations of mercury have been hard to characterize. We now demonstrate that subtoxic concentrations of HgCl2 can potently (maximal at 1 μM) increase Ras. GTP levels in Jurkat, a human T cell line. Remarkably, this activation of Ras occurs without a concomitant increase in MAP kinase activation, suggesting that mercury may direct Ras into a nonproductive state. In addition to its direct effect on Ras, concentrations of HgCl2 as low as 0.6 μM inhibited the ability of the T cell receptor to activate Ras and MAP kinase. The inhibitory effect of mercury is selective, as activation of MAP kinase by phorbol diesters remain intact. Since the Ras/MAP kinase pathway is both highly conserved and central to signal transduction processes mediated by a myriad of diverse membrane receptor systems in a variety of cell types, these results suggest a mechanism for adverse health effects resulting from exposure to low levels of mercury. They also support a model for regulation of the Ras/MAP kinase pathway, whereby partial but unproductive activation of Ras can diminish signaling from cell surface receptors.
KW - Map kinase
KW - Mercury
KW - Ras
KW - T cell receptor
UR - http://www.scopus.com/inward/record.url?scp=0035516589&partnerID=8YFLogxK
U2 - 10.1006/taap.2001.9272
DO - 10.1006/taap.2001.9272
M3 - 文章
C2 - 11714248
AN - SCOPUS:0035516589
SN - 0041-008X
VL - 176
SP - 162
EP - 168
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 3
ER -