Changes in the Proteome after Neuronal Zif268 Overexpression
Changes in the Proteome after Neuronal Zif268 Overexpression
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DOI：
10.1021/pr801000r
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发表时间：
2009-07-01
影响因子：
4.4
通讯作者：
Mansuy, Isabelle M.
中科院分区：
文献类型：
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作者：
Baumgaertel, Karsten;Tweedle-Cullen, Ry Y.;Mansuy, Isabelle M.
大脑可塑性的持久形式是长期记忆的细胞基础，它们的紊乱是痴呆和认知障碍等病理状况的基础。神经元可塑性是一个复杂的过程，它利用细胞质和细胞核中的分子级联反应，并涉及许多转录因子，特别是立即早期基因（IEGs）。控制IEG的信号级联反应已经得到了很好的描述，但下游的转录反应却知之甚少，尤其是其晚期成分。在这里，我们研究了IEG Zif 268 m在成人大脑中诱导的与长期记忆相关的反应。使用Zif268神经元表达增加的小鼠模型，导致记忆改善，我们确定了由Zif268表达调控的蛋白质集合，并根据其启动子中存在的共有结合基序区分直接和间接靶点。我们发现，Zif268调节许多底物具有不同的生物功能，包括蛋白质修饰和降解（蛋白酶体核心复合物），磷酸化，细胞分裂，感觉知觉，代谢和金属离子转运。这些结果提供了一个全面的定量数据集，描述了成年小鼠大脑中Zif268依赖性蛋白质组的特征，并为IEGs下游的活性依赖性途径提供了具有生物学意义的新见解。
Long-lasting forms of brain plasticity are a cellular basis for long-term memory, and their disturbance underlies pathological conditions such as dementia and cognitive impairment. Neuronal plasticity is a complex process that utilizes molecular cascades in the cytoplasm and the nucleus and involves numerous transcription factors, in particular, immediate early genes (IEGs). The signaling cascades that control IEGs are fairly well described, but the downstream transcriptional response is poorly understood, especially its late components. Here, we investigated the response induced by the IEG Zif268m the adult brain in relation to long-term memory. Using a mouse model with increased neuronal expression of Zif268 that leads to improved memory, we identified an ensemble of proteins regulated by Zif268 expression and differentiated between direct and indirect targets based on the presence of a consensus binding motif in their promoter. We show that Zif268 regulates numerous substrates with diverse biological functions including protein modification and degradation (proteasome-core complex), phosphorylation, cell division, sensory perception, metabolism, and metal ion transport. The results provide a comprehensive and quantitative data set characterizing the Zif268-dependent proteome in the adult mouse brain and offers biologically important new insight into activity-dependent pathways downstream of IEGs.