Regulation of fosB and ΔfosB rnRNA expression:: In vivo and in vitro studies
Regulation of fosB and ΔfosB rnRNA expression:: In vivo and in vitro studies
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DOI：
10.1016/j.brainres.2007.01.069
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发表时间：
2007-04-27
期刊：
影响因子：
2.9
通讯作者：
Nestler, Eric J.
中科院分区：
文献类型：
--
作者：
Alibhai, Imran N.;Green, Thomas A.;Nestler, Eric J.
转录因子Delta FosB是FosB的截短剪接异构体，在几种类型的慢性刺激后在大脑中积累。这种积累被认为是由Delta FosB相对于所有其他Fos家族蛋白独特的稳定性所介导的。本研究的目的是确定这两种FosB亚型的相对表达是否也在mRNA水平上受到调控，从而进一步促进慢性刺激后Delta FosB的选择性积累。首先，与蛋白质不同的是，在体外培养的细胞和体内的脑中，Delta FosB mRNA的半衰期仅略长于全长FosB mRNA。此外，与c-fos类似，两种FosB亚型在急性给予苯丙胺或应激后在纹状体内大量诱导，在慢性暴露后部分脱敏。令人惊讶的是，在急性而不是慢性刺激后，Delta FosB与FosB mRNA的相对比率增加最为显著。最后，在培养细胞中过表达调节RNA剪接的多嘧啶结合蛋白(PTB1)，与FosB mRNA相比，Delta FosB的相对表达减少。综上所述，这些发现表明，FosB前-mRNA的剪接受到剪接机械可获得的未剪接转录物数量的调节。这些数据提供了关于Delta FosB mRNA产生的基本信息，并表明在慢性刺激下Delta FosB蛋白的选择性积累不涉及其通过RNA剪接优先产生。(C)2007 Elsevier B.V.保留所有权利。
The transcription factor Delta FosB, a truncated splice isoform of FosB, accumulates in brain after several types of chronic stimulation. This accumulation is thought to be mediated by the unique stability of Delta FosB compared to all other Fos family proteins. The goal of the present study was to determine if the relative expression of the two fosB isoforms is also regulated at the mRNA level, thereby further contributing to the selective accumulation of Delta FosB after chronic stimulation. First, unlike the protein, the half-life of Delta fosB mRNA is only slightly longer than that of full-length fosB mRNA both in cultured cells in vitro and in the brain in vivo. Additionally, similar to c-fos, both fosB isoforms are induced abundantly in striatum after acute administration of amphetamine or stress, and partially desensitize after chronic exposures. Surprisingly, the relative ratio of Delta fosB to fosB mRNA increases most significantly after acute, not chronic, stimulation. Finally, overexpression of polypyrimidine tract binding protein (PTB1), which regulates RNA splicing, in cultured cells decreases the relative expression of Delta fosB compared to fosB mRNA. Together, these findings suggest that splicing of fosB pre-mRNA is regulated by the quantity of unspliced transcript available to the splicing machinery. These data provide fundamental information concerning the generation of Delta fosB mRNA, and indicate that the selective accumulation of Delta FosB protein with chronic stimulation does not involve its preferential generation by RNA splicing. (c) 2007 Elsevier B.V. All rights reserved.