Induced focal adhesion kinase expression suppresses apoptosis by activating NF-κB signaling in intestinal epithelial cells
Induced focal adhesion kinase expression suppresses apoptosis by activating NF-κB signaling in intestinal epithelial cells
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DOI：
10.1152/ajpcell.00450.2005
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发表时间：
2006-05-01
影响因子：
5.5
通讯作者：
Wang, JY
中科院分区：
文献类型：
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作者：
Zhang, HFM;Keledjian, KM;Wang, JY
Focal adhesion kinase （FAK）整合多种细胞外和细胞内信号，参与多种生物学功能，但其在肠上皮细胞（IECs）凋亡调控中的确切作用和下游靶向信号尚不清楚。目前的研究验证了FAK通过改变NF-kappa B信号传导在IEC-6细胞系中具有抗凋亡作用的假设。通过稳定转染野生型(WT)-FAK基因诱导FAK表达，增加FAK磷酸化，这与NF-kappa B活性增加有关。当这些稳定的wt - fak转染的IECs暴露于tnf - α加环己亚胺（tnf - α /CHX）时，也表现出对凋亡的抗性增加。含有I κ B α超抑制因子的重组腺病毒载体对nf - κ B的特异性抑制可阻止wt - fak转染细胞对凋亡的抗性增加。相反，通过异位表达FAK的显性阴性突变体（DNM-FAK）使FAK失活，抑制NF-kappa B活性，增加对tnf - α / chx诱导的细胞凋亡的敏感性。此外，通过消耗细胞多胺诱导内源性FAK的表达增加了NF-kappa B的活性，并导致对TNF-kappa/ chx诱导的细胞凋亡的抗性增强，这两种情况都可以通过过表达DNM-FAK来阻止。这些结果表明，FAK表达的增加至少部分地通过激活IECs中nf - κ B信号传导抑制tnf - α / chx诱导的细胞凋亡。
Focal adhesion kinase (FAK) integrates various extracellular and intracellular signals and is implicated in a variety of biological functions, but its exact role and downstream targeting signals in the regulation of apoptosis in intestinal epithelial cells (IECs) remains unclear. The current study tested the hypothesis that FAK has an antiapoptotic role in the IEC-6 cell line by altering NF-kappa B signaling. Induced FAK expression by stable transfection with the wild-type (WT)-FAK gene increased FAK phosphorylation, which was associated with an increase in NF-kappa B activity. These stable WT-FAK-transfected IECs also exhibited increased resistance to apoptosis when they were exposed to TNF-alpha plus cycloheximide (TNF-alpha/CHX). Specific inhibition of NF-kappa B by the recombinant adenoviral vector containing the I kappa B alpha superrepressor prevented increased resistance to apoptosis in WT-FAK-transfected cells. In contrast, inactivation of FAK by ectopic expression of dominant-negative mutant of FAK (DNM-FAK) inhibited NF-kappa B activity and increased the sensitivity to TNF-alpha/CHX-induced apoptosis. Furthermore, induced expression of endogenous FAK by depletion of cellular polyamines increased NF-kappa B activity and resulted in increased resistance to TNF-kappa/CHX-induced apoptosis, both of which were prevented by overexpression of DNM-FAK. These results indicate that increased expression of FAK suppresses TNF-alpha/CHX-induced apoptosis, at least partially, through the activation of NF-kappa B signaling in IECs.