TY - JOUR
T1 - Activation of methionine synthase by insulin-like growth factor-1 and dopamine
T2 - A target for neurodevelopmental toxins and thimerosal
AU - Waly, M.
AU - Olteanu, H.
AU - Banerjee, R.
AU - Choi, S. W.
AU - Mason, J. B.
AU - Parker, B. S.
AU - Sukumar, S.
AU - Shim, S.
AU - Sharma, A.
AU - Benzecry, J. M.
AU - Power-Charnitsky, V. A.
AU - Deth, R. C.
PY - 2004/4
Y1 - 2004/4
N2 - Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu2+ promoted enzyme activity and methylation, while Cu+, Pb2+, Hg2+ and Al3+ were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC50 of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.
AB - Methylation events play a critical role in the ability of growth factors to promote normal development. Neurodevelopmental toxins, such as ethanol and heavy metals, interrupt growth factor signaling, raising the possibility that they might exert adverse effects on methylation. We found that insulin-like growth factor-1 (IGF-1)- and dopamine-stimulated methionine synthase (MS) activity and folate-dependent methylation of phospholipids in SH-SY5Y human neuroblastoma cells, via a PI3-kinase- and MAP-kinase-dependent mechanism. The stimulation of this pathway increased DNA methylation, while its inhibition increased methylation-sensitive gene expression. Ethanol potently interfered with IGF-1 activation of MS and blocked its effect on DNA methylation, whereas it did not inhibit the effects of dopamine. Metal ions potently affected IGF-1 and dopamine-stimulated MS activity, as well as folate-dependent phospholipid methylation: Cu2+ promoted enzyme activity and methylation, while Cu+, Pb2+, Hg2+ and Al3+ were inhibitory. The ethylmercury-containing preservative thimerosal inhibited both IGF-1- and dopamine-stimulated methylation with an IC50 of 1 nM and eliminated MS activity. Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury, aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.
KW - Attention deficit hyperactivity disorder
KW - Autism
KW - D4 dopamine receptor
KW - DNA methylation
KW - Lead
KW - Mercury
KW - P13-kinase
KW - Phospholipid methylation
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U2 - 10.1038/sj.mp.4001476
DO - 10.1038/sj.mp.4001476
M3 - Article
C2 - 14745455
AN - SCOPUS:11144357815
SN - 1359-4184
VL - 9
SP - 358
EP - 370
JO - Molecular psychiatry
JF - Molecular psychiatry
IS - 4
ER -