Jin Hyeon-Ok, Seo Sung-Keum, Woo Sang-Hyeok, Kim Eun-Sung, Lee Hyung-Chahn, Yoo Doo-Hyun, Choe Tae-Boo, Hong Seok-Il, Kim Jong-Il, Park In-Chul
Division of Cancer Radiation Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
FEBS Lett. 2009 Jan 5;583(1):123-7. doi: 10.1016/j.febslet.2008.11.035. Epub 2008 Dec 6.
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.
据报道，SP600125（SAPK抑制剂II）作为c-Jun氨基末端激酶（JNK）的可逆ATP竞争性抑制剂发挥作用。在本研究中，我们发现，通过下游靶点S6K1和S6磷酸化水平降低评估，SP600125可诱导mTOR活性呈剂量依赖性降低，并且Redd1表达显著增加。用小干扰RNA（siRNA）敲低Redd1表达可使SP600125导致的S6磷酸化降低得以恢复。过表达激活转录因子4（ATF4）可上调Redd1表达，而用siRNA抑制ATF4表达则通过下调SP600125诱导的Redd1表达增加来提高S6磷酸化水平。这些结果共同表明，SP600125通过ATF4诱导的Redd1表达增加来抑制mTOR活性。
