Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases.
Cisplatin-mediated activation of extracellular signal-regulated kinases 1/2 (ERK1/2) by inhibition of ERK1/2 phosphatases.
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DOI：
10.1111/j.1471-4159.2008.05550.x
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发表时间：
2008-09
影响因子：
4.7
通讯作者：
Hetman, Michal
中科院分区：
文献类型：
--
作者：
Gozdz, Agata;Vashishta, Aruna;Kalita, Katarzyna;Szatmari, Erzsebet;Zheng, Jing-Juan;Tamiya, Shigeo;Delamere, Nicholas A.;Hetman, Michal
神经退行性变相关激活ERK1/2的机制(S)仍然知之甚少。我们报道，在培养的大脑皮层神经元中，ERK1/2的基础磷酸化需要NMDAR(NMDAR)，神经毒性DNA嵌入药物顺铂通过NMDAR增加ERK1/2的磷酸化，但降低其活性。顺铂使ERK1/2去磷酸化速率降低。顺铂处理的神经元表现出普遍的转录抑制，可能与ERK1/2选择性磷酸酶的表达减少有关，其中包括双特异性磷酸酶6(DUSP6)和DUSP3激活剂痘苗相关激酶3(VRK3)。因此，顺铂对ERK1/2的作用可能与转录调节的磷酸酶抑制ERK1/2的缺陷有关。事实上，转录抑制剂放线菌素-D减少了DUSP6和VRK3的表达，同时诱导了依赖NMDAR的ERK1/2激活和ERK1/2去磷酸化障碍。因此，顺铂介导的ERK1/2磷酸酶转录抑制有助于延迟和持久地积累由基础NMDAR活性驱动的磷酸化ERK1/2。我们的结果首次为转录调控的神经元ERK/2失活提供了直接证据。它的破坏可能与神经退行性变相关的ERK1/2的激活有关。
The mechanism(s) underlying neurodegeneration-associated activation of ERK1/2 remain poorly understood. We report that in cultured rat cortical neurons, whose basal ERK1/2 phosphorylation required NMDA receptors (NMDAR), the neurotoxic DNA intercalating drug cisplatin increased ERK1/2 phosphorylation via NMDAR despite reducing their activity. The rate of ERK1/2 dephosphorylation was lowered by cisplatin. Cisplatin-treated neurons showed general transcription inhibition likely accounting for the reduced expression of the ERK1/2-selective phosphatases including the dual specificity phosphatase-6 (DUSP6) and the DUSP3 activator vaccinia-related kinase-3 (VRK3). Hence, cisplatin effects on ERK1/2 may be due to the deficient ERK1/2 inhibition by the transcription-regulated phosphatases. Indeed, the transcription inhibitor actinomycin-D reduced expression of DUSP6 and VRK3 while inducing the NMDAR-dependent activation of ERK1/2 and the impairment of ERK1/2 dephosphorylation. Thus, cisplatin-mediated transcriptional inhibition of ERK1/2 phosphatases contributed to delayed and long lasting accumulation of phospho-ERK1/2 that was driven by the basal NMDAR activity. Our results provide the first direct evidence for transcriptionally-regulated inactivation of neuronal ERK/2. Its disruption likely contributes to neurodegeneration-associated activation of ERK1/2.
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DOI：
10.1042/bj20071512
发表时间：
2008-06-01
期刊：
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影响因子：
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DOI：
10.1083/jcb.148.2.283
发表时间：
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期刊：
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影响因子：
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作者：
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影响因子：
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