Chronic Fos-Related Antigens: Stable Variants of ΔFosB Induced in Brain by Chronic Treatments
Chronic Fos-Related Antigens: Stable Variants of ΔFosB Induced in Brain by Chronic Treatments
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慢性 Fos 相关抗原：慢性治疗在大脑中诱导的 ΔFosB 稳定变体
作者：
Jingshan Chen;M. Kelz;B. Hope;Y. Nakabeppu;E. Nestler
Fos家族转录因子被认为在大脑对各种刺激的转录反应中起重要作用。先前的研究描述了35和37 kDa fos样蛋白，称为慢性fos相关抗原（FRAs），它们以特定区域的方式在大脑中诱导，以响应几种慢性扰动，包括慢性电惊厥发作，精神药物治疗和病变。我们在这项研究中表明，慢性fra是ΔFosB的同工型，ΔFosB是FosB的截断剪接变体，由于其稳定性，在慢性治疗后在大脑中积累。ΔFosB cDNA编码来自单个AUG翻译起始位点的33,35和37kda蛋白的表达。35和37 kDa蛋白对应于慢性治疗在大脑中诱导的慢性fra，而33 kDa蛋白对应于急性治疗在大脑中诱导的fos样蛋白，这一发现基于抗fra和抗fosb抗体在一维和二维Western blots上的迁移。利用四环素调控的基因表达系统控制ΔFosB或FosB表达的细胞，我们发现37 kDa ΔFosB蛋白具有非常长的半衰期，35 kDa ΔFosB蛋白具有中间半衰期，33 kDa ΔFosB蛋白和所有FosB衍生蛋白具有相对较短的半衰期。此外，我们发现33 kDa ΔFosB蛋白是ΔFosB表达激活后首先出现的蛋白。最后，ΔFosB蛋白被证明具有dna结合活性，并在报告基因检测中发挥有效的反激活作用。总之，这些发现支持了一种方案，其中ΔFosB作为33 kDa蛋白表达，被修饰成35和37 kDa的高度稳定的同工型。结果，这些稳定的同种异构体通过反复治疗逐渐在大脑中积累，以介导长期的神经和行为可塑性。
Fos family transcription factors are believed to play an important role in the transcriptional responses of the brain to a variety of stimuli. Previous studies have described 35 and 37 kDa Fos-like proteins, termed chronic Fos-related antigens (FRAs), that are induced in brain in a region-specific manner in response to several chronic perturbations, including chronic electroconvulsive seizures, psychotropic drug treatments, and lesions. We show in this study that the chronic FRAs are isoforms of ΔFosB, a truncated splice variant of FosB that accumulate in brain after chronic treatments because of their stability. ΔFosB cDNA encodes the expression of 33, 35, and 37 kDa proteins that arise from a single AUG translation start site. The 35 and 37 kDa proteins correspond to the chronic FRAs that are induced in brain by chronic treatments, whereas the 33 kDa protein corresponds to a Fos-like protein that is induced in brain by acute treatments, findings based on migration on one- and two-dimensional Western blots with anti-FRA and anti-FosB antibodies. Using cells in which ΔFosB or FosB expression is under the control of a tetracycline-regulated gene expression system, we show that the 37 kDa ΔFosB protein exhibits a remarkably long half-life, the 35 kDa ΔFosB protein exhibits an intermediate half-life, and the 33 kDa ΔFosB protein and all FosB-derived proteins exhibit relatively short half-lives. Moreover, we show that the 33 kDa ΔFosB protein is the first to appear after activation of ΔFosB expression. Finally, ΔFosB proteins are shown to possess DNA-binding activity and to exert potent transactivating effects in reporter gene assays. Together, these findings support a scheme wherein ΔFosB, expressed as a 33 kDa protein, is modified to form highly stable isoforms of 35 and 37 kDa. As a result, these stable isoforms gradually accumulate in the brain with repeated treatments to mediate forms of long-lasting neural and behavioral plasticity.
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DOI：
10.1073/pnas.89.13.5764
发表时间：
1992-07-01
影响因子：
11.1
作者：
HOPE, B;KOSOFSKY, B;NESTLER, EJ
通讯作者：
NESTLER, EJ
影响因子：
56.9
作者：
ROGERS, S;WELLS, R;RECHSTEINER, M
通讯作者：
RECHSTEINER, M
影响因子：
3.6
作者：
J. Chen;H. E. Nye;M. Kelz;N. Hiroi;Y. Nakabeppu;B. Hope;E. Nestler
通讯作者：
J. Chen;H. E. Nye;M. Kelz;N. Hiroi;Y. Nakabeppu;B. Hope;E. Nestler
可卡因在纹状体和伏隔核中调节慢性 FOS 相关抗原诱导的药理学研究。
DOI：
--
发表时间：
1995
期刊：
The Journal of pharmacology and experimental therapeutics.
影响因子：
--
作者：
Nye,HE;Hope,BT;Kelz,MB;Iadarola,M;Nestler,EJ
通讯作者：
Nestler,EJ
DOI：
10.1073/pnas.92.14.6522
发表时间：
1995-07-03
影响因子：
11.1
作者：
SHOCKETT, P;DIFILIPPANTONIO, M;SCHATZ, DG
通讯作者：
SCHATZ, DG