Finco T S, Westwick J K, Norris J L, Beg A A, Der C J, Baldwin A S
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
J Biol Chem. 1997 Sep 26;272(39):24113-6. doi: 10.1074/jbc.272.39.24113.
Ras proteins function in stimulating cell proliferation and differentiation through the activation of Raf-dependent and Raf-independent signal transduction pathways and the subsequent activation of specific transcription factors. The transcription factor NF-kappaB has been widely studied as a regulator of genes involved in immune and inflammatory responses. A variety of stimuli activate NF-kappaB through the induced phosphorylation and degradation of the inhibitor IkappaB followed by nuclear translocation of NF-kappaB. We show here that oncogenic forms of Ha-Ras activate NF-kappaB, not through induced nuclear translocation, but rather through the activation of the transcriptional function of the NF-kappaB RelA/p65 subunit. Importantly, RelA/p65 -/- cells are inefficient in the activation of kappaB-dependent gene expression in response to oncogenic Ras expression. Furthermore, IkappaBalpha expression blocks focus formation in NIH3T3 cells induced by oncogenic Ras. These results demonstrate that NF-kappaB is a critical downstream mediator of Ha-Ras signaling and oncogenic potential.
Ras蛋白通过激活依赖Raf和不依赖Raf的信号转导途径以及随后激活特定转录因子来刺激细胞增殖和分化。转录因子NF-κB作为参与免疫和炎症反应的基因的调节因子已被广泛研究。多种刺激通过诱导抑制剂IkappaB的磷酸化和降解，随后NF-κB的核转位来激活NF-κB。我们在此表明，致癌形式的Ha-Ras激活NF-κB，不是通过诱导核转位，而是通过激活NF-κB RelA/p65亚基的转录功能。重要的是，RelA/p65 -/-细胞在响应致癌Ras表达时激活κB依赖性基因表达的效率低下。此外，IkappaBalpha表达可阻断致癌Ras诱导的NIH3T3细胞中的集落形成。这些结果表明，NF-κB是Ha-Ras信号传导和致癌潜力的关键下游介质。
