Intracellular signaling pathways involved in mediating the effects of lead on the transcription factor Sp1
Intracellular signaling pathways involved in mediating the effects of lead on the transcription factor Sp1
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DOI：
10.1016/s0736-5748(03)00067-4
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发表时间：
2003-08-01
影响因子：
1.8
通讯作者：
Zawia, NH
中科院分区：
文献类型：
--
作者：
Atkins, DS;Basha, MR;Zawia, NH
众所周知，在大脑发育的关键时期接触铅会导致认知和行为缺陷。尽管 Ph 诱导发育神经毒性的机制尚不清楚，但它可能涉及生长和分化所必需的基因转录的改变。最近的研究表明，Pb 通过作用于转录因子 Sp1 来干扰生长和分化。 Pb 诱导的 Sp1 活性变化可能是信号转导途径中间体改变的结果。这项研究在体内和体外检查了信号因子在介导 Pb 对 Sp1 DNA 结合的影响中的作用。对铅暴露大鼠的海马发育特征进行了监测，其中包括 Sp1 DNA 结合、PKC 和 MAPK 蛋白水平。 Pb 暴露导致 PND 5-10 期间 SpI DNA 结合诱导，随后在 PND 15-20 期间下降。 PKC(x 和 MAPK 的蛋白质表达谱遵循相对相似的模式。为了检查 Sp1 DNA 结合、PKCα 和 MAPK 之间的相互依赖性，将 PC12 细胞暴露于 Pb 和/或 NGF。Pb 或 NGF 暴露增加了 Sp1 DNA 结合。添加 PKC 抑制剂（十字孢菌素）减弱了 NGF 和 Pb 诱导的 Sp1 DNA 结合，而 MAPK 抑制剂 (PD 98059) 完全这些发现表明 SpI DNA 结合受 PKC 和 MAPK 调节，Pb 可以通过它们间接调节 SpI DNA 结合。 (C) 2003 ISDN 出版，Elsevier Ltd. 保留所有权利。
It has been well established that exposure to Pb during critical periods of brain development results in both cognitive and behavioral deficits. Although the mechanism by which Ph induces developmental neurotoxicity is unknown, it may involve alterations in transcription of genes that are essential for growth and differentiation. Recent studies reveal that Pb interferes with growth and differentiation by acting on the transcription factor Sp1. Pb-induced changes in the activity of Sp1 may be consequent to alterations in intermediates in signal transduction pathways. This study examines both in vivo and in vitro the role of signaling factors in mediating the effects of Pb on Sp1 DNA-binding. Hippocampal developmental profiles of Sp1 DNA-binding, PKC, and MAPK protein levels were monitored in Pb-exposed rats. Pb exposure resulted in an induction of SpI DNA-binding during PND 5-10 followed by a subsequent decline on PND 15-20. The protein expression profiles for PKC(x and MAPK followed a relatively similar pattern. To examine the interdependence between Sp1 DNA-binding, PKCalpha, and MAPK, PC12 cells were exposed to Pb and/or NGF. Pb or NGF exposure increased Sp1 DNA-binding. Addition of the PKC inhibitor (staurosporine) diminished NGF and Pb-induced Sp1 DNA-binding, while the MAPK inhibitor (PD 98059), completely abolished both basal and induced SpI DNA-binding. These findings demonstrate that SpI DNA-binding is regulated by PKC and MAPK, which may serve as mediators through which Pb may indirectly modulate SpI DNA-binding. (C) 2003 ISDN. Published by Elsevier Ltd. All rights reserved.