Arsura M, FitzGerald M J, Fausto N, Sonenshein G E
Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118-2394, USA.
Cell Growth Differ. 1997 Oct;8(10):1049-59.
Treatment of hepatocytes with transforming growth factor beta1 (TGF-beta1) induces growth arrest, which is followed by extensive cell death by apoptosis. Previously, we found that TGF-beta1 down-modulates nuclear factor (NF)-kappaB/Rel activity in murine B cell lymphomas, inducing apoptosis. Furthermore, p65 (RelA)-deficient mice died during gestation due to apoptosis of liver cells. Here we have explored the effects of TGF-beta1 on hepatocytes, using two untransformed murine hepatocyte cell lines, AML-12 and NMH, which constitutively express classical NF-kappaB. TGF-beta1 treatment caused increased NF-kappaB binding that was followed by a dramatic decrease in NF-kappaB levels that preceded apoptosis. Ectopic c-Rel expression ablated apoptosis induced by TGF-beta1. The down-regulation in NF-kappaB activity correlated with elevated IkappaB-alpha expression due to hypophosphorylation and increased IkappaB-alpha protein stability. Thus, NF-kappaB factor expression acts directly to promote liver cell survival. Furthermore, these findings characterize a novel signaling pathway for TGF-beta1 in epithelial cells involving down-regulation of NF-kappaB/Rel factors activity through posttranslational modification of IkappaB-alpha protein.
用转化生长因子β1（TGF-β1）处理肝细胞会诱导生长停滞，随后发生广泛的细胞凋亡。此前，我们发现TGF-β1下调小鼠B细胞淋巴瘤中的核因子（NF）-κB/Rel活性，从而诱导凋亡。此外，p65（RelA）缺陷小鼠在妊娠期因肝细胞凋亡而死亡。在此，我们利用两种组成性表达经典NF-κB的未转化小鼠肝细胞系AML-12和NMH，探究了TGF-β1对肝细胞的影响。TGF-β1处理导致NF-κB结合增加，随后在凋亡之前NF-κB水平急剧下降。异位表达c-Rel可消除TGF-β1诱导的凋亡。NF-κB活性的下调与因低磷酸化导致的IκB-α表达升高以及IκB-α蛋白稳定性增加相关。因此，NF-κB因子表达直接促进肝细胞存活。此外，这些发现揭示了TGF-β1在上皮细胞中的一种新信号通路，该通路涉及通过IκB-α蛋白的翻译后修饰下调NF-κB/Rel因子活性。
