Inability of transforming growth factor-β to cause SnoN degradation leads to resistance to transforming growth factor-β-induced growth arrest in esophageal cancer cells
Inability of transforming growth factor-β to cause SnoN degradation leads to resistance to transforming growth factor-β-induced growth arrest in esophageal cancer cells
复制标题
DOI：
10.1158/0008-5472.can-04-4354
复制
发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Lebman, DA
中科院分区：
文献类型：
--
作者：
Edmiston, JS;Yeudall, WA;Lebman, DA
众所周知，对转化生长因子-β (TGF-β) 的生长抑制反应丧失是包括食道癌在内的上皮癌的一个共同特征。然而，人们对废除这一关键稳态机制的分子基础知之甚少。在对 TGF-β 诱导的生长抑制具有抵抗力的食管癌细胞系中，尽管存在功能性信号传导成分，TGF-β 也无法降低 c-myc 的转录。因此，为了更好地了解导致对 TGF-β 诱导的生长停滞产生抗性的机制，研究了无法减少 c-myc 转录的基础。无论对 TGF-β 诱导的生长停滞的敏感性如何，TGF-β 都增强了 Smad3 蛋白复合物结合 c-myc 调节元件的能力。然而，在生长抑制耐药的食管癌细胞系中，Smad3 蛋白复合物含有 SnoN 癌蛋白。此外，在对 TGF-β 诱导的生长停滞有抵抗力的食道癌细胞系中，TGF-β 不会引起 SnoN 的降解。对生长抑制敏感和生长抑制抵抗细胞系中 SnoN 表达调节效果的分析表明，SnoN 的降解是 TGF-β 诱导的 c-myc 转录抑制和生长停滞的先决条件。数据表明，SnoN-Smad3 复合物不会抑制 c-myc 转录，而是阻止活性阻遏物复合物的功能。因此，这些研究揭示了食管癌中抵抗 TGF-β 诱导的生长抑制的新机制，即无法降解 SnoN。此外，他们还表明 SnoN 可以阻断 TGF-β 对基因转录的抑制。
It is well established that loss of a growth inhibitory response to transforming growth factor-beta (TGF-beta) is a common feature of epithelial cancers including esophageal cancer. However, the molecular basis for the abrogation of this key homeostatic mechanism is poorly understood. In esophageal cancer cell lines that are resistant to TGF-beta-induced growth inhibition, TGF-beta also fails to decrease transcription of c-myc despite the presence of functional signaling components. Consequently, to gain a better understanding of the mechanisms leading to resistance to TGF-beta-induced growth arrest, the basis for the inability to decrease c-myc transcription was investigated. Regardless of sensitivity to TGF-beta-induced growth arrest, TGF-beta enhanced the ability of Smad3-protein complexes to bind c-myc regulatory elements. However, in a growth inhibition-resistant esophageal cancer cell line, the Smad3-protein complexes contained the SnoN oncoprotein. Furthermore, in esophageal cancer cell lines that are resistant to TGF-beta-induced growth arrest, TGF-beta does not cause degradation of SnoN. Analyses of the effect of modulating SnoN expression in both growth inhibition-sensitive and growth inhibition-resistant cell lines showed that degradation of SnoN is a prerequisite for both TGF-beta-induced repression of c-myc transcription and growth arrest. The data indicate that SnoN-Smad3 complexes do not cause repression of c-myc transcription but rather prevent functionality of active repressor complexes. Thus, these studies reveal a novel mechanism for resistance to TGF-beta-induced growth inhibition in esophageal cancer, namely the failure to degrade SnoN. In addition, they show that SnoN can block TGF-beta repression of gene transcription.