Methamphetamine causes coordinate regulation of Src, Cas, Crk, and the Jun N-terminal kinase-Jun pathway
Methamphetamine causes coordinate regulation of Src, Cas, Crk, and the Jun N-terminal kinase-Jun pathway
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DOI：
10.1124/mol.61.5.1124
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发表时间：
2002-05-01
影响因子：
3.6
通讯作者：
Cadet, JL
中科院分区：
文献类型：
--
作者：
Jayanthi, S;McCoy, MT;Cadet, JL
甲基苯丙胺（METH）的临床滥用是一个主要问题，因为它可以在人类中引起持久的神经退行性影响。这些并发症的分子机制的当前概念集中在活性氧的形成。在此，我们提供了cDNA微阵列证据，METH给药引起c-Jun和其他参与导致c-Jun活化的途径的成员的诱导[应激活化蛋白激酶/Jun N-末端激酶（JNK 3），Crk相关底物-Cas和c-Src]在环境应激或细胞因子刺激后。逆转录-聚合酶链反应分析证实了这些增加，也表明，JNK 1和JNK 3的表达，但不是JNK 2也增加了在METH治疗的小鼠。Western blot分析显示METH增加了丝氨酸-63和丝氨酸-73残基磷酸化的c-Jun的表达。JNK通路的其他上游成员，包括磷酸化JNK、促分裂原活化蛋白激酶激酶4、促分裂原活化蛋白激酶激酶7、Crk II、Cas和c-Src也在蛋白水平上增加。这些值在药物治疗后1周恢复至基线。这些结果进行了讨论，他们的支持的JNK/Jun通路的激活在METH的病理生理效应的可能作用。
The clinical abuse of methamphetamine (METH) is a major concern because it can cause long-lasting neurodegenerative effects in humans. Current concepts of the molecular mechanisms underlying these complications have centered on the formation of reactive oxygen species. Herein, we provide cDNA microarray evidence that METH administration caused the induction of c-Jun and of other members involved in the pathway leading to c-Jun activation [stress-activated protein kinase/Jun N-terminal kinase (JNK3), Crk-associated substrate-Cas and c-Src] after environmental stresses or cytokine stimulation. Reverse transcription-polymerase chain reaction analysis confirmed these increases and also showed that the expression of JNK1 and JNK3 but not JNK2 was also increased in the METH-treated mice. Western blot analysis showed that METH increased the expression of c-Jun phosphorylated at serine-63 and serine-73 residues. Other upstream members of the JNK pathway, including phosphorylated JNKs, mitogen-activated protein kinase kinase 4, mitogen-activated protein kinase kinase 7, Crk II, Cas, and c-Src were also increased at the protein level. These values returned to baseline by 1 week after drug treatment. These results are discussed in terms of their support for a possible role of the activation of the JNK/Jun pathway in the pathophysiological effects of METH.