Reduction of transforming growth factor-β type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma
Reduction of transforming growth factor-β type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma
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DOI：
10.1002/ijc.25164
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发表时间：
2010-10-01
影响因子：
6.4
通讯作者：
Hishida, Akira
中科院分区：
文献类型：
--
作者：
Fukasawa, Hirotaka;Yamamoto, Tatsuo;Hishida, Akira
虽然转化生长因子- β (tgf - β)信号的失调与肾癌的发生有关，但其在肾细胞癌（RCC）中的确切机制尚不清楚，在我们的研究中，我们研究了smad药物治疗的tgf - β信号通路及其在RCC患者手术样本中的调节机制。我们发现，与正常肾组织相比，核磷酸化Smad2的免疫反应性在RCC中显著降低，从而提示tgf - β信号在RCC组织中减弱。鉴于Smad4的转录下调和tgf - β -II型受体（T β R-II）的转录后下调在RCC中经常发现，我们研究了T β R-II的降解和泛素化活性。我们发现，蛋白酶体介导的T β R-II降解和泛素化在RCC组织中均显著增强。此外，我们发现Smad泛素化调节因子2 （Smurf2）和T β R-II E3连接酶的水平在临床分期较高的RCC患者组织中较正常组织升高，且与T β R-II水平呈负相关。我们的研究结果表明，低的T β R-II蛋白水平是由于通过Smurf2增强的泛素依赖性降解，可能参与了RCC中tgf - β信号通路的衰减。
Although dysregulation of transforming growth factor-beta (TGF-beta) signalling is implicated in renal carcinogenesis, its precise mechanism is unknown in renal cell carcinoma (RCC) in our study, we investigated Smad-medicated TGF-beta signalling pathway and its regulatory mechanisms in surgical samples from patients with RCC. We found that immunoreactivity for nuclear phosphorylated Smad2 was significantly decreased in RCC compared to normal renal tissues, thereby TGF-beta signaling was suggested to be attenuated in RCC tissues. In accordance with the result transcriptional downregulation of Smad4 and post-transcriptional downregulation of TGF-beta type II receptor (T beta R-II) were frequently found in RCC, we investigated the activities of degradation and ubiquitination of T beta R-II. We found that both proteasome-mediated degradation and ubiquitination of T beta R-II were markedly enhanced in RCC tissues. Moreover, we found that the level of Smad ubiquitination regulatory factor 2 (Smurf2), and the E3 ligase for T beta R-II, was increased in RCC tissues of the patients with higher clinical stages compared to the normal tissues and was inversely correlated with the levels of T beta R-II. Our results suggest that the low T beta R-II protein level is due to augmented ubiquitin-dependent degradation via Smurf2 and might be involved in the attenuation of TGF-beta signaling pathway in RCC.