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MAPK and mTOR pathways are involved in cadmium‐induced neuronal apoptosis
Author(s) -
Chen Long,
Liu Lei,
Luo Yan,
Huang Shile
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.05133.x
Subject(s) - pi3k/akt/mtor pathway , p38 mitogen activated protein kinases , mapk/erk pathway , microbiology and biotechnology , kinase , p70 s6 kinase 1 , neurodegeneration , apoptosis , signal transduction , biology , protein kinase a , phosphorylation , chemistry , biochemistry , medicine , disease
Cadmium (Cd) may be accumulated in human body through long‐term exposure to Cd‐polluted environment, resulting in neurodegeneration and other diseases. To study the mechanism of Cd‐induced neurodegeneration, PC12 and SH‐SY5Y cells were exposed to Cd. We observed that Cd‐induced apoptosis in the cells in a time‐ and concentration‐dependent manner. Cd rapidly activated the mitogen‐activated protein kinases (MAPK) including extracellular signal‐regulated kinase 1/2 (Erk1/2), c ‐Jun N‐terminal kinase (JNK) and p38. Inhibition of Erk1/2 and JNK, but not p38, partially protected the cells from Cd‐induced apoptosis. Consistently, over‐expression of dominant negative c‐ Jun or down‐regulation of Erk1/2, but not p38 MAPK, partially prevented Cd‐induced apoptosis. To our surprise, Cd also activated mammalian target of rapamycin (mTOR)‐mediated signaling pathways. Treatment with rapamycin, an mTOR inhibitor, blocked Cd‐induced phosphorylation of S6K1 and eukaryotic initiation factor 4E binding protein 1, and markedly inhibited Cd‐induced apoptosis. Down‐regulation of mTOR by RNA interference also in part, rescued cells from Cd‐induced death. These findings indicate that activation of the signaling network of MAPK and mTOR is associated with Cd‐induced neuronal apoptosis. Our results strongly suggest that inhibitors of MAPK and mTOR may have a potential for prevention of Cd‐induced neurodegeneration.