1. SP600125 negatively regulates the mammalian target of rapamycin via ATF4-induced Redd1 expression
- Author
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Sung-Keum Seo, Hyeon-Ok Jin, Tae-Boo Choe, Eun Sung Kim, Doo-Hyun Yoo, Sang-Hyeok Woo, Hyung-Chahn Lee, Seok-Il Hong, Jong-Il Kim, and In-Chul Park
- Subjects
endocrine system ,Biophysics ,P70-S6 Kinase 1 ,Biochemistry ,Downregulation and upregulation ,Structural Biology ,polycyclic compounds ,Genetics ,Humans ,ATF4 ,RNA, Small Interfering ,Molecular Biology ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Anthracenes ,Mitogen-Activated Protein Kinase Kinases ,Sirolimus ,SP600125 ,Gene knockdown ,Mammalian target of rapamycin ,Chemistry ,Kinase ,TOR Serine-Threonine Kinases ,Cell Biology ,respiratory system ,Molecular biology ,Activating Transcription Factor 4 ,Redd1 ,Phosphorylation ,JNK ,Protein Kinases ,HeLa Cells ,Transcription Factors - Abstract
SP600125 (SAPK Inhibitor II) is reported to function as a reversible ATP competitive inhibitor of c-Jun N-terminal kinase (JNK). In the present study, we show that SP600125 induces a dose-dependent decrease in mTOR activity, as assessed by reduced phosphorylation of the downstream targets S6K1 and S6, and a significant increase in the expression of Redd1. Knockdown of Redd1 expression by siRNA resulted in a recovery of decreased S6 phosphorylation by SP600125. Overexpression of ATF4 upregulated the expression of Redd1, while suppression of ATF4 expression by siRNA enhanced the level of S6 phosphorylation by downregulating the SP600125-induced increase in Redd1 expression. Together, these results indicate that SP600125 inhibits mTOR activity via an ATF4-induced increase in Redd1 expression.
- Published
- 2008