Ray Ramesh M, Bavaria Mitul, Johnson Leonard R
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Cell Signal. 2015 Sep;27(9):1850-9. doi: 10.1016/j.cellsig.2015.06.002. Epub 2015 Jun 17.
Tissue polyamine levels are largely determined by the activity of ornithine decarboxylase (ODC, EC 4.1.17), which catalyzes the conversion of ornithine to the diamine putrescine. The activity of the enzyme is primarily regulated by a negative feedback mechanism involving ODC antizyme (AZ). Our previous studies demonstrated that AZ synthesis is stimulated by the absence of amino acids, the levels of which are sensed by the mTOR complex containing TORC1, which is stimulated by amino acids and inhibited by their absence, and TORC2 the function of which is not well defined. Polyamines, which cause a +1 ribosomal frameshift during the translation of AZ mRNA are required to increase AZ synthesis in both the presence and absence of amino acids. Amino acid starvation increases TORC2 activity. We have demonstrated that mTORC2 activity is necessary for AZ synthesis in the absence of amino acids. Tuberous sclerosis protein (TSC), a negative regulator of mTOR function regulates the activities of both the TORC1 and TORC2. TSC2 knockdown increased mTORC1 activity with concomitant inhibition of mTORC2 activity eliminating AZ induction in the absence of amino acids as well as that induced by spermidine. Thus, these results clearly demonstrate that in addition to polyamines, mTORC2 activity is necessary for AZ synthesis. Moreover, our results support a role for mTORC2 in the synthesis of a specific protein, AZ, which regulates growth of intestinal epithelial cells.
组织多胺水平在很大程度上由鸟氨酸脱羧酶（ODC，EC 4.1.17）的活性决定，该酶催化鸟氨酸转化为二胺腐胺。该酶的活性主要通过涉及ODC反义酶（AZ）的负反馈机制进行调节。我们之前的研究表明，氨基酸缺乏会刺激AZ的合成，氨基酸水平由包含TORC1的mTOR复合物感知，TORC1受氨基酸刺激，在氨基酸缺乏时受到抑制，而TORC2的功能尚不清楚。多胺在AZ mRNA翻译过程中会导致核糖体+1移码，无论有无氨基酸存在，都需要多胺来增加AZ的合成。氨基酸饥饿会增加TORC2的活性。我们已经证明，在缺乏氨基酸的情况下，mTORC2的活性对于AZ的合成是必需的。结节性硬化蛋白（TSC）是mTOR功能的负调节因子，可调节TORC1和TORC2的活性。敲低TSC2会增加mTORC1的活性，同时抑制mTORC2的活性，从而消除在缺乏氨基酸以及由亚精胺诱导时的AZ诱导。因此，这些结果清楚地表明，除了多胺之外，mTORC2的活性对于AZ的合成也是必需的。此外，我们的结果支持mTORC2在合成一种特定蛋白质AZ中的作用，AZ可调节肠上皮细胞的生长。
