The Met protooncogene is a transcriptional target of NF kappaB: implications for cell survival.
The Met protooncogene is a transcriptional target of NF kappaB: implications for cell survival.
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DOI：
10.1002/jcb.22226
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发表时间：
2009-08-15
影响因子：
4
通讯作者：
Zarnegar, Reza
中科院分区：
文献类型：
--
作者：
Dai, James Y.;DeFrances, Marie C.;Zou, Chunbin;Johnson, Carla J.;Zarnegar, Reza
NF κ B转录因子响应于细胞外刺激如TNF α调节基因表达。由NF κ B调控的基因编码控制细胞生长和存活的蛋白质。Met是肝细胞生长因子的酪氨酸激酶受体，它也促进细胞有丝分裂和存活。以前，我们发现Met基因表达受TNF α调节。在这份报告中，我们确定和表征的肿瘤坏死因子α反应元件的Met启动子。该元件含有与NF κ B位点相邻的串联C/EBP位点。NF κ B p65亚基和C/EBP β与该元件的结合由TNF α诱导。为了检查NF κ B和Met在体内的相互作用，我们确定了与对照相比，Met mRNA和蛋白质水平在p65-/-小鼠的肝脏中降低。在p65-/-小鼠胚胎成纤维细胞（MEF）中，与对照组相比，TNF α对Met的诱导作用被消除，而Met的基础基因表达减少了一半。当在p65-/- MEFs中过表达时，Met赋予对TNF α介导的细胞死亡的抗性。相反，野生型MEFs中显性失活Met的表达使其对TNF α诱导的细胞死亡敏感。在用siRNA处理以敲低内源性Met的肝细胞中观察到TNF α攻击后的类似应答。总之，这些结果表明Met基因是NF κ B的直接靶标，并且Met参与NF κ B介导的细胞存活。
NFkappaB transcription factor regulates gene expression in response to extracellular stimuli such as TNF alpha. The genes regulated by NFkappaB encode for proteins which control cell growth and survival. Met is the tyrosine kinase receptor for hepatocyte growth factor, and it too promotes cell mitogenesis and survival. Previously, we showed that Met gene expression is regulated by TNF alpha. In this report, we identify and characterize a TNF alpha response element in the Met promoter. This element contains tandem C/EBP sites adjacent to an NFkappaB site. Binding of the NFkappaB p65 subunit and C/EBP beta to this element is induced by TNF alpha. To examine the interplay of NFkappaB and Met in vivo, we determined that Met mRNA and protein levels are reduced in the livers of p65-/- mice as compared to controls. In p65-/- mouse embryonic fibroblasts (MEFs), Met induction by TNF alpha is abrogated while Met's basal gene expression is reduced by half as compared to controls. When overexpressed in p65-/- MEFs, Met confers resistance to TNF alpha mediated cell death. Conversely, expression of dominant negative Met in wildtype MEFs renders them sensitive to cell death induced by TNF alpha. A similar response following TNF alpha challenge was observed in hepatocytic cells treated with siRNA to knockdown endogenous Met. Together, these results indicate that the Met gene is a direct target of NFkappaB and that Met participates in NFkappaB-mediated cell survival.
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DOI：
10.1073/pnas.93.9.4213
发表时间：
1996-04-30
影响因子：
11.1
作者：
Epstein, JA;Shapiro, DN;Maas, RL
通讯作者：
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影响因子：
9.7
作者：
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作者：
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DOI：
10.1073/pnas.0403412101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Borowiak, M;Garratt, AN;Birchmeier, C
通讯作者：
Birchmeier, C
影响因子：
8
作者：
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通讯作者：
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