Notch signaling induces cell cycle arrest in small cell lung cancer cells.
Notch signaling induces cell cycle arrest in small cell lung cancer cells.
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发表时间：
2001-04
期刊：
影响因子：
11.2
通讯作者：
V. Sriuranpong;M. Borges;R. Ravi;D. R. Arnold;B. Nelkin;S. Baylin;D. Ball
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文献类型：
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作者：
V. Sriuranpong;M. Borges;R. Ravi;D. R. Arnold;B. Nelkin;S. Baylin;D. Ball
在人类肺癌的各种形式中，小细胞肺癌（SCLC）表现出特征性的神经内分泌（NE）表型。 SCLC 中的神经和 NE 分化部分取决于碱性螺旋-环-螺旋 (bHLH) 转录因子人 achaete-scute 同源物-1 (hASH1) 的作用。在神经系统发育中，Notch 信号通路是 bHLH 因子（包括 hASH1）的关键负调节因子，控制细胞命运决定和分化。为了表征 SCLC 中 Notch 通路的功能，我们探讨了培养的 SCLC 细胞中组成型活跃的 Notch 信号传导的后果。使用重组腺病毒在 DMS53 和 NCI-H209 SCLC 细胞中过表达 Notch1、Notch2 或 Notch 效应蛋白人毛增强子 split-1 (HES1) 的活性形式。 Notch 蛋白（而非 HES1 或对照腺病毒）引起了与 G1 细胞周期阻滞相关的严重生长停滞。我们发现 p21(waf1/cip1) 和 p27kip1 的上调与细胞周期的变化一致。活性Notch蛋白还导致hASH1表达显着减少，以及磷酸化细胞外信号调节激酶(ERK)1和ERK2的显着激活，这些发现已被证明与SCLC细胞的细胞周期停滞相关。这些数据表明，先前描述的 Notch 蛋白作为原癌基因的功能是高度依赖于背景的。在高度增殖的 hASH1 依赖性 NE 肿瘤中，Notch 激活可能与生长停滞和肿瘤潜力的明显降低有关。
Among the various forms of human lung cancer, small cell lung cancer (SCLC) exhibits a characteristic neuroendocrine (NE) phenotype. Neural and NE differentiation in SCLC depend, in part, on the action of the basic-helix-loop-helix (bHLH) transcription factor human achaete-scute homologue-1 (hASH1). In nervous system development, the Notch signaling pathway is a critical negative regulator of bHLH factors, including hASH1, controlling cell fate commitment and differentiation. To characterize Notch pathway function in SCLC, we explored the consequences of constitutively active Notch signaling in cultured SCLC cells. Recombinant adenoviruses were used to overexpress active forms of Notch1, Notch2, or the Notch effector protein human hairy enhancer of split-1 (HES1) in DMS53 and NCI-H209 SCLC cells. Notch proteins, but not HES1 or control adenoviruses, caused a profound growth arrest, associated with a G1 cell cycle block. We found up-regulation of p21(waf1/cip1) and p27kip1 in concert with the cell cycle changes. Active Notch proteins also led to dramatic reduction in hASH1 expression, as well as marked activation of phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2, findings that have been shown to be associated with cell cycle arrest in SCLC cells. These data suggest that the previously described function of Notch proteins as proto-oncogenes is highly context-dependent. Notch activation, in the setting of a highly proliferative hASH1-dependent NE neoplasm, can be associated with growth arrest and apparent reduction in neoplastic potential.