SP600125 negatively regulates the mammalian target of rapamycin via ATF4-induced Redd1 expression.
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.
Jin
Hyeon-Ok
HO
Division of Cancer Radiation Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Seo
Sung-Keum
SK
Woo
Sang-Hyeok
SH
Kim
Eun-Sung
ES
Lee
Hyung-Chahn
HC
Yoo
Doo-Hyun
DH
Choe
Tae-Boo
TB
Hong
Seok-Il
SI
Kim
Jong-Il
JI
Park
In-Chul
IC
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000873:Anthracenes / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000096:biosynthesis*
C497109:ATF4 protein, human; D000873:Anthracenes; C469991:DDIT4 protein, human; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051701:Activating Transcription Factor 4; C432165:pyrazolanthrone; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020123:Sirolimus