Selenite Inhibits the c-Jun N-terminal Kinase/Stress-activated Protein Kinase (JNK/SAPK) through a Thiol Redox Mechanism

Hee-Sae Park,Eun Park,Mi-Sung Kim,Kwangseog Ahn,Ick Young Kim,Eui-Ju Choi

doi:10.1074/jbc.275.4.2527

Abstract

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.

Highlights

Selenium, an essential trace element present in both prokaryotic and eukaryotic cells, has been linked to regulatory functions in cell growth, cell survival, cytotoxicity, and transformation [1,2,3,4,5,6,7]
Selenite Represses the JNK and p38 Pathways but Not the ERK Pathway—To investigate a possible role of selenite in the regulation of intracellular signaling cascades, we examined whether selenite could modulate mitogen-activated protein kinase (MAPK) activation processes
We observed that exposure of 293T cells to 100 nM selenite resulted in suppression of the UV-stimulated activities of either JNK1 or p38 MAPK (Fig. 1), whereas it did not affect ERK2 activity

Summary

Introduction

An essential trace element present in both prokaryotic and eukaryotic cells, has been linked to regulatory functions in cell growth, cell survival, cytotoxicity, and transformation [1,2,3,4,5,6,7]. The mitogen-activated protein kinase (MAPK) pathway is one of the most widely studied signaling pathways involved in the transduction of intracellular signals initiated by extracellular stimuli to the nucleus. The physiological functions of JNK or p38 MAPK are not yet clear, but they seem to be involved in stress-activated cellular events that under certain conditions can include cell death [23, 24, 33,34,35,36,37]. We found that selenite exerts distinct effects on the ERK, JNK, and p38 MAPK signaling pathways. Differential regulation of the MAPK pathways by selenite may be important to understand the mechanism by which selenite can modulate the intracellular signaling cascades and, exert its effects on various cellular events

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