2-aminopurine inhibits leptin receptor signal transduction
2-aminopurine inhibits leptin receptor signal transduction
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DOI：
10.1016/j.ejphar.2006.09.044
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发表时间：
2006-12-28
影响因子：
5
通讯作者：
Nomura, Yasuyuki
中科院分区：
文献类型：
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作者：
Hosoi, Toru;Matsunami, Naomi;Nomura, Yasuyuki
瘦素是调节食物摄入和体重的重要循环信号。在本研究中，我们研究了2-氨基嘌呤（2-AP），一种双链RNA激活蛋白激酶（PKR）的抑制剂，对瘦素信号转导的影响。2-AP剂量依赖性地抑制瘦素诱导的稳定转染Ob-Rb瘦素受体的HEK 293细胞中信号转导和转录激活因子3（STAT 3）、细胞外信号调节激酶（ERK）和c-Jun N-末端激酶（JNK）的磷酸化。另一方面，我们观察到只有轻微的抑制瘦素诱导的STAT 3激活嘌呤处理，表明抑制作用将显着增强氨基的存在下。2-AP不抑制PMA诱导的ERK激活，表明该效应可能是瘦素信号特异性的。2-AP的抑制作用不是由新合成的蛋白质介导的，因为2-AP对瘦素诱导的STAT 3激活的抑制作用在蛋白质合成抑制剂放线菌酮的存在下没有被废除。有趣的是，瘦素没有诱导PKR激活，表明2-AP对瘦素信号的影响可能不依赖于PKR。最后，2-AP抑制瘦素诱导的Ob-Rb瘦素受体的磷酸化。这些结果提供了2-AP的新作用的证据，即，在Ob-Rb瘦素受体水平抑制瘦素信号转导的活化。(c)2006 Elsevier B. V.保留所有权利。
Leptin is an important circulating signal for the regulation of food intake and body weight. In the present study, we investigated the effect of 2-aminopurine (2-AP), an inhibitor of double-strand RNA-activated protein kinase (PKR), on leptin signal transduction. 2-AP dose-dependently inhibited the leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) in HEK293 cells stably transfected with the Ob-Rb leptin receptor. On the other hand, we observed only slight inhibition of leptin-induced STAT3 activation by purine treatment, indicating that the inhibitory effect will be dramatically enhanced in the presence of an amino group. 2-AP did not inhibit PMA-induced ERK activation, indicating that the effect may be leptin-signal specific. The inhibitory effect of 2-AP was not mediated by newly synthesized protein because the inhibitory effect of 2-AP on leptin-induced STAT3 activation was not abrogated in the presence of the protein synthesis inhibitor cycloheximide. Interestingly, leptin did not induce PKR activation, suggesting that the effect of 2-AP on the leptin signal may be independent of PKR. Finally, 2-AP inhibited leptin-induced phosphorylation of the Ob-Rb leptin receptor. These results provide evidence of a novel action of 2-AP, i.e., inhibition of the activation of leptin signal transduction at the level of the Ob-Rb leptin receptor. (c) 2006 Elsevier B.V. All rights reserved.