Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappa B and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways
Tumor necrosis factor alpha-induced E-selectin expression is activated by the nuclear factor-kappa B and c-JUN N-terminal kinase/p38 mitogen-activated protein kinase pathways
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DOI：
10.1074/jbc.272.5.2753
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发表时间：
1997-01-31
影响因子：
4.8
通讯作者：
Collins, T
中科院分区：
文献类型：
--
作者：
Read, MA;Whitley, MZ;Collins, T
内皮细胞表达E-选择素对炎症反应过程中白细胞的募集至关重要。肿瘤坏死因子α（TNF α）对E-选择素启动子的转录调节需要多个核因子-κ B（NF-κ B）结合位点和一个cAMP-应答元件/激活转录因子样结合位点，称为阳性结构域II（PDII）。在这里，我们的特点的作用，应激激活的家庭的促分裂原活化蛋白（MAP）激酶诱导表达的粘附分子。通过UV交联和免疫沉淀，我们证明了转录因子ATF-2和c-JUN的异源二聚体与PDII位点组成性结合。内皮细胞的TNF α刺激诱导ATF-2和c-JUN的瞬时磷酸化，并诱导c-JUN N-末端激酶（JNK 1）和p38的显著活化，但不诱导细胞外信号调节激酶（ERK 1）的显著活化。JNK和p38组成性地存在于细胞核中，并且DNA结合的c-JUN和ATF-2分别被JNK和p38稳定地接触。MAP/ERK激酶激酶1（MEKK 1）是MAP激酶的上游激活剂，其增加E-选择素启动子转录，并且需要完整的PDII位点以实现最大诱导。MEKK 1还可以激活NF-κ B依赖性基因表达。显性干扰形式的JNK/p38信号通路的影响表明，这些激酶的激活是至关重要的精氨酸诱导的E-选择素基因表达。因此，TNF α激活两种信号传导途径，NF-κ B和JNK/p38，这两种途径都是E-选择素最大表达所需的。
E-selectin expression by endothelium is crucial for leukocyte recruitment during inflammatory responses. Transcriptional regulation of the E-selectin promoter by tumor necrosis factor alpha (TNF alpha) requires multiple nuclear factor-kappa B (NF-kappa B) binding sites and a cAMP-responsive element/activating transcription factor-like binding site designated positive domain II (PDII). Here we characterize the role of the stress-activated family of mitogen-activated protein (MAP) kinases in induced expression of this adhesion molecule. By UV cross-linking and immunoprecipitation, we demonstrated that a heterodimer of transcription factors ATF-2 and c-JUN is constitutively bound to the PDII site. TNF alpha stimulation of endothelial cells induces transient phosphorylation of both ATF-2 and c-JUN and induces marked activation of the c-JUN N-terminal kinase (JNK1) and p38 but not extracellular signal-regulated kinase (ERK1). JNK and p38 are constitutively present in the nucleus, and DNA-bound c-JUN and ATF-2 are stably contacted by JNK and p38, respectively. MAP/ERK kinase kinase 1 (MEKK1), an upstream activator of MAP kinases, increases E-selectin promoter transcription and requires an intact PDII site for maximal induction. MEKK1 can also activate NF-kappa B -dependent gene expression. The effects of dominant interfering forms of the JNK/p38 signaling pathway demonstrate that activation of these kinases is critical for cytokine-induced E-selectin gene expression. Thus, TNF alpha activates two signaling pathways, NF-kappa B and JNK/p38, which are both required for maximal expression of E-selectin.