Selenite inhibits the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) through a thiol redox mechanism.
Selenium, an essential biological trace element, has been shown to modulate functions of many regulatory proteins involved in signal transduction and to affect a variety of cellular activities including cell growth, survival, and death. The molecular mechanism by which selenium exerts its action on the cellular events, however, remains unclear. In our present study, we observed that selenite suppresses both the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase pathway in 293T cells. In contrast, selenite had little effect on the extracellular signal-regulated kinase pathway. Furthermore, selenite directly inhibited JNK/SAPK activity in vitro but not the p38 activity. The in vitro inhibition of JNK/SAPK by selenite was reversed by the addition of reducing agents such as dithiothreitol and beta-mercaptoethanol. Replacement of cysteine 116 in JNK1 by serine abolished the inhibitory effect of selenite on JNK1 activity both in vitro and in vivo. Selenite also suppressed a c-Jun-dependent luciferase reporter activity stimulated through the JNK signaling pathway. Taken together, our findings strongly suggest that selenite differentially modulates the mammalian mitogen-activated protein kinase pathways and that it can repress the JNK/SAPK signaling pathway by inhibiting JNK/SAPK through a thiol redox mechanism.
Park
H S
HS
National Creative Research Initiative Center for Cell Death, Korea University, Anam-dong, Sungbuk-ku, Seoul, 136-701, Korea.
Park
E
E
Kim
M S
MS
Ahn
K
K
Kim
I Y
IY
Choi
E J
EJ
D001483:Base Sequence; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D010084:Oxidation-Reduction; D015398:Signal Transduction; D018038:Sodium Selenite / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*
D017931:DNA Primers; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D018038:Sodium Selenite; D003545:Cysteine