Small molecule screening identifies regulators of the transcription factor ΔFosB.
Small molecule screening identifies regulators of the transcription factor ΔFosB.
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小分子筛选可识别转录因子 ÎFosB 的调节因子。
DOI：
10.1021/cn3000235
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发表时间：
2012
影响因子：
5
通讯作者：
Rudenko,Gabby
中科院分区：
文献类型：
--
作者：
Wang,Yun;Cesena,TeresaI;Ohnishi,Yoko;Burger-Caplan,Rebecca;Lam,Vivian;Kirchhoff,PaulD;Larsen,ScottD;Larsen,MarthaJ;Nestler,EricJ;Rudenko,Gabby
ΔFosB蛋白在纹状体中积累以响应滥用药物、左旋多巴或压力的长期给药，引发持久的神经和行为变化，这些变化是药物成瘾、异常不自主运动（运动障碍）和抑郁症的基础。ΔFosB结合在许多基因启动子中发现的AP-1 DNA共有序列，可以抑制或激活基因转录。在纹状体中，ΔFosB被认为与JunD二聚化形成功能性转录因子，尽管引人注目的是JunD并不平行积累。一种解释是ΔFosB可以招募不同的伴侣，包括它自己，这取决于它被诱导的神经元类型和慢性刺激，产生对基因转录有不同影响的蛋白质复合物。为了开发研究ΔFosB的化学探针，进行了高通量筛选以鉴定调节ΔFosB功能的小分子。两种具有低微摩尔活性的化合物，称为C2和C6，通过不同的机制破坏ΔFosB与DNA的结合，并且在体外测定中刺激Δ FosB介导的转录。在可卡因处理的小鼠中，C2特异性地显著提高AMPA谷氨酸受体GluR 2亚基的mRNA水平，GluR 2亚基是ΔFosB的已知靶基因，在药物成瘾和内源性恢复机制中发挥作用。C2和C6对ΔFosB同源二聚体和ΔFosB/JunD异源二聚体具有不同的活性，表明这些化合物可用作探针，研究不同的Δ FosB复合物对生物系统中基因转录调控的贡献，并评估ΔFosB作为治疗靶点的效用。
ΔFosB protein accumulates in the striatum in response to chronic administration of drugs of abuse, L-DOPA, or stress, triggering long lasting neural and behavioral changes that underlie aspects of drug addiction, abnormal involuntary movements (dyskinesia), and depression. ΔFosB binds AP-1 DNA consensus sequences found in promoters of many genes and can both repress or activate gene transcription. In the striatum, ΔFosB is thought to dimerize with JunD to form a functional transcription factor, though strikingly JunD does not accumulate in parallel. One explanation is that ΔFosB can recruit different partners, including itself, depending on the neuron type in which it is induced and the chronic stimulus, generating protein complexes with different effects on gene transcription. To develop chemical probes to study ΔFosB, a high-throughput screen was carried out to identify small molecules that modulate ΔFosB function. Two compounds with low micromolar activity, termed C2 and C6, disrupt the binding of ΔFosB to DNA via different mechanisms, and in in vitro assays stimulate ΔFosB-mediated transcription. In cocaine-treated mice, C2 significantly elevates mRNA levels of the AMPA glutamate receptor GluR2 subunit with specificity, a known target gene of ΔFosB that plays a role in drug addiction and endogenous resilience mechanisms. C2 and C6 show different activities against ΔFosB homodimers compared to ΔFosB/JunD heterodimers, suggesting that these compounds can be used as probes to study the contribution of different ΔFosB-containing complexes on the regulation of gene transcription in biological systems and to assess the utility of ΔFosB as a therapeutic target.