The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway
The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway
复制标题
DOI：
10.1038/sj.bjp.0703534
复制
发表时间：
2000-09-01
影响因子：
7.3
通讯作者：
Vellenga, E
中科院分区：
文献类型：
--
作者：
Birkenkamp, KU;Tuyt, LML;Vellenga, E
1在本研究中，我们研究了p38丝裂原活化蛋白(MAP)激酶通路在介导核因子-kappa B(nf-kappa B)转录活性中的可能作用。在用磷酸酶抑制剂冈田酸(okadaic acid，OA)刺激的红白血病细胞系TF-1.2 tf-1细胞中，p38磷酸化水平的升高与p38-kappa B和GAL4p65调节的转录活性增强有关。然而，瞬时转染实验表明，用p38 MAPK特异性抑制剂SB203580(1MU M)预处理或过表达MKK3或MKK6的激酶缺陷型突变体并不影响OA增强的NF-kappa B转录活性。事实上，5和10 mU M SB203580不是抑制而是增强了NF-kappa B介导的启动子活性2倍，这与p65亚基的磷酸化无关。3 SB203580介导的转录活性的增加与细胞外信号调节激酶1/2和c-jun氨基末端激酶的磷酸化增强有关，而与p38激酶无关。4属于ERK1/2、JNK和p38通路的激酶缺陷突变体的过表达表明，只有显性负向的Raf-L抑制了SB203580抑制的NF-kappa B活性。这可能表明ERK1/2通路参与了SB203580对NF-kappa B介导的基因转录的增强作用。5本研究证明p38 MAPK通路不参与OA诱导的NF-kappa B的激活。SB203580在较高浓度时激活ERK通路，从而增强NF-kappa B的转录活性。
1 In the present study we investigated a possible role for the p38 mitogen-activated protein (MAP) kinase pathway in mediating nuclear factor-kappa B (NF-kappa B) transcriptional activity in the erythroleukaemic cell line TF-1.2 TF-1 cells stimulated with the phosphatase inhibitor okadaic acid (OA) demonstrated enhanced NF-kappa B and GAL4p65-regulated transcriptional activity which was associated with elevated p38 phosphorylation. However, pretreatment with the p38 MAPK specific inhibitor SB203580 (1 mu M) or overexpression of kinase-deficient mutants of MKK3 or MKK6 did not affect OA-enhanced NF-kappa B transcriptional potency, as determined in transient transfection assays. In fact, 5 and 10 mu M SB203580 enhanced rather than inhibited NF-kappa B-mediated promoter activity by 2 fold, which was independent of phosphorylation of the p65 subunit.3 The SB203580-mediated increase in NF-kappa B transcriptional activity was associated with enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and c-Jun N-terminal kinase (JNK), but not p38 kinase.4 Overexpression of kinase-deficient mutants belonging to the ERK1/2, JNK, and p38 pathways showed that only dominant-negative Raf-l abrogated SB203580-enhanced NF-kappa B activity. This would implicate the involvement of the ERK1/2 pathway in the enhancing effects of SB203580 on NF-kappa B-mediated gene transcription.5 This study demonstrates that the p38 MAP kinase pathway is not involved in the OA-induced activation of NF-kappa B. SB203580 at higher concentrations activates the ERK pathway, which subsequently enhances NF-kappa B transcriptional activity.