Evidence for a role of Smad3 and Smad2 in stabilization of the tumor-derived mutant Smad2.Q407R
Evidence for a role of Smad3 and Smad2 in stabilization of the tumor-derived mutant Smad2.Q407R
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DOI：
10.1074/jbc.m212496200
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发表时间：
2003-07-04
影响因子：
4.8
通讯作者：
Théret, N
中科院分区：
文献类型：
--
作者：
Dumont, E;Lallemand, F;Théret, N
转化生长因子 β (TGF-β) 是细胞增殖的有效抑制剂，对 TGF-β 反应性的丧失可能会导致人类癌症的发生。在肝细胞癌中，TGF-β 信号传导作为肿瘤抑制途径的潜在作用可以通过编码 TGF-β 受体的基因或该信号传导的下游成分（例如 Smad2）中存在的突变来说明。尽管 Smad2 在肝细胞癌中发生突变，但 TGF-β 信号传导与肿瘤进展相关的变化仍有待确定。使用 HepG2 肝癌细胞，我们在此显示了 Smad2 的表达。 Q407R 是在人肝细胞癌中发现的错义突变，在增强 TGF-β 诱导 Mix 转录的能力方面，其效果不如野生型 Smad2 的表达。 2 发起人。这种效应与 Smad2 稳态水平的降低特别相关。 Q407R，大概是因为它通过蛋白酶体机制增强了泛素化和降解。更重要的是，我们发现Smad2的不稳定。当该突变体在细胞内与野生型 Smad2 发生同源寡聚化或与 Smad3 发生异源寡聚化时，Q407R 被逆转。因此，我们的研究结果使我们能够提出一种新的机制来抑制肿瘤衍生的 Smad2 突变的有害作用，这种突变的缺失可能导致肿瘤发生过程中细胞增殖失调。
Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation and the loss of responsiveness to TGF-beta may contribute to the development of human cancers. In hepatocellular carcinomas, the potential role of TGF-beta signaling as a tumor suppressor pathway can be illustrated by the presence of mutations in genes encoding TGF-beta receptors or downstream components of this signaling such as Smad2. Although Smad2 is mutated in hepatocellular carcinomas, the alteration of TGF-beta signaling with respect to tumor progression remains to be established. Using the HepG2 hepatoma cells, we showed here that expression of Smad2. Q407R, a missense mutation found in human hepatocellular carcinoma, was less effective than expression of wild-type Smad2 in enhancing the ability of TGF-beta to induce transcription from the Mix. 2 promoter. This effect was specifically associated with a decrease in the steady-state level of Smad2. Q407R, presumably because of an enhancement of its ubiquitination and degradation through the proteasome machinery. More importantly, we found that the unstability of Smad2. Q407R was reversed when this mutant undergoes homo-oligomerization with wild-type Smad2 or hetero-oligomerization with Smad3 within the cells. Therefore, our findings allowed us to propose a novel mechanism for suppression of the deleterious effect of a tumor-derived mutation of Smad2, which loss may lead to dysregulated cell proliferation during tumorigenesis.