Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts
Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts
复制标题
DOI：
10.1093/jn/137.8.1857
复制
发表时间：
2007-08-01
影响因子：
4.2
通讯作者：
Lynch, Christopher J.
中科院分区：
文献类型：
--
作者：
Vary, Thomas C.;Deiter, Gina;Lynch, Christopher J.
进食通过增强活性真核起始因子 (eIF)4F 复合物的组装来刺激蛋白质合成的信使 RNA 翻译起始阶段，从而促进心肌中的蛋白质合成。本文报道的实验检查了雷帕霉素敏感信号通路在增加膳食喂养期间活性 eIF4G-eIF4E 复合物形成中的潜在作用。在使用或不使用雷帕霉素（一种哺乳动物雷帕霉素靶蛋白 (mTOR) 复合物 1 的抑制剂）治疗的情况下，在餐前和餐后 3 小时对喂食由大鼠未纯化饮食组成的膳食的雄性 Sprague-Dawley 大鼠的心脏进行取样。雷帕霉素可防止膳食喂养引起的心肌蛋白质合成刺激。用雷帕霉素抑制 mTOR 会降低雷帕霉素相关 TOR 蛋白与 mTOR 的关联，并阻止进食诱导的 eIF4G-eIF4E 复合物组装。相比之下，eIF4E 结合蛋白-1 (4E-BP1)-eIF4E 复合物的丰度不受膳食喂养或雷帕霉素的影响。雷帕霉素预处理完全阻止了进食诱导的 eIF4G(Ser(1108)) 磷酸化，而抑制剂仅部分减弱了进食诱导的 70-kDa 核糖体蛋白 S6 激酶 1 (Thr(389)) 磷酸化和 4E-BP1 γ 形式的程度。进食诱导的蛋白激酶 B 在 Ser(473) 或 Thr(308) 上的磷酸化不受雷帕霉素的影响。这些发现表明，膳食喂养后 eIF4G 的磷酸化程度是通过心肌中的雷帕霉素敏感机制发生的。此外，雷帕霉素敏感的 eIF4G 磷酸化减少也可能导致活性 eIF4G-eIF4E 复合物的形成减少。
Feeding promotes protein synthesis in cardiac muscle through a stimulation of the messenger RNA translation initiation phase of protein synthesis by enhancing assembly of active eukaryotic initiation factor (eIF)4F complex. The experiments reported herein examined the potential role for a rapamycin-sensitive signaling pathway in increasing formation of active eIF4G-eIF4E complex during meal feeding. Hearts from male Sprague-Dawley rats fed a meal consisting of rat nonpurified diet were sampled prior to and 3 h following the meal in the presence or absence of treatment with rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) complex 1. Rapamycin prevented the meal feeding-induced stimulation of myocardial protein synthesis. Inhibition of mTOR with rapamycin decreased the association of rapamycin-associated TOR protein with mTOR and prevented the feeding-induced assembly of eIF4G-eIF4E complex. In contrast, the abundance of eIF4E binding protein-1 (4E-BP1)-eIF4E complex was unaffected by either meal feeding or rapamycin. Pretreatment with rapamycin completely prevented the feeding-induced phosphorylation of eIF4G(Ser(1108)), whereas the inhibitor only partially attenuated meal feeding-induced 70-kDa ribosomal protein S6 kinase1 (Thr(389)) phosphorylation and extent of 4E-BP1 in the gamma-form. Meal feeding-induced phosphorylation of protein kinase B on either Ser(473) or Thr(308) was unaffected by rapamycin. These findings suggest the extent of phosphorylation of eIF4G following meal feeding occurs by a rapamycin-sensitive mechanism in cardiac muscle. Furthermore, the rapamycin-sensitive reductions in phosphorylation of eIF4G may also lead to decreased formation of active eIF4G-eIF4E complex.