Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation.
Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-{beta} and STAT3 activation.
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STAT5的损失通过增加TGF- {beta}和STAT3激活引起肝纤维化和癌症的发展。
DOI：
10.1084/jem.20080003
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发表时间：
2009-04-13
期刊：
影响因子：
--
通讯作者：
Hennighausen L
中科院分区：
文献类型：
--
作者：
Hosui A;Kimura A;Yamaji D;Zhu BM;Na R;Hennighausen L
肝细胞癌发生的分子机制尚未完全清楚。肝脏特异性信号转导子和转录激活子（STAT）5A/B缺失小鼠（STAT 5-LKO）用四氯化碳（CCl 4）处理，组织学分析显示肝纤维化和肿瘤。CCl 4处理后，STAT 5-LKO小鼠肝组织中转化生长因子（TGF）-β水平和STAT 3活性升高。为了确定STAT 5沉默和TGF-β上调以及STAT 3激活之间的分子联系，我们检查了STAT 5缺失的小鼠胚胎成纤维细胞和原代肝细胞。这些细胞显示TGF-β蛋白水平升高，而信使RNA水平几乎保持不变。蛋白酶抑制剂研究表明，STAT 5缺陷增强了成熟TGF-β的稳定性。免疫沉淀和免疫组织化学分析表明，STAT 5，通过其N-末端序列，可以结合TGF-β和逆转录病毒介导的过表达STAT 5降低TGF-β水平。为了证实STAT 5的N末端结构域的体内意义，我们用CCl 4处理表达缺少N末端的STAT 5（STAT 5-ΔN）的小鼠。STAT 5-ΔN小鼠发生CCl 4诱导的肝纤维化，但没有肿瘤。总之，STAT 5的缺失导致TGF-β水平升高和生长激素诱导的STAT 3活性增强。我们认为STAT 5-TGF-β-STAT 3网络失调有助于慢性肝病的发展。
The molecular mechanisms underlying the development of hepatocellular carcinoma are not fully understood. Liver-specific signal transducer and activator of transcription (STAT) 5A/B–null mice (STAT5-LKO) were treated with carbon tetrachloride (CCl4), and histological analyses revealed liver fibrosis and tumors. Transforming growth factor (TGF)–β levels and STAT3 activity were elevated in liver tissue from STAT5-LKO mice upon CCl4 treatment. To define the molecular link between STAT5 silencing and TGF-β up-regulation, as well as STAT3 activation, we examined STAT5-null mouse embryonic fibroblasts and primary hepatocytes. These cells displayed elevated TGF-β protein levels, whereas messenger RNA levels remained almost unchanged. Protease inhibitor studies revealed that STAT5 deficiency enhanced the stability of mature TGF-β. Immunoprecipitation and immunohistochemistry analyses demonstrated that STAT5, through its N-terminal sequences, could bind to TGF-β and that retroviral-mediated overexpression of STAT5 decreased TGF-β levels. To confirm the in vivo significance of the N-terminal domain of STAT5, we treated mice that expressed STAT5 lacking the N terminus (STAT5-ΔN) with CCl4. STAT5-ΔN mice developed CCl4-induced liver fibrosis but no tumors. In conclusion, loss of STAT5 results in elevated TGF-β levels and enhanced growth hormone–induced STAT3 activity. We propose that a deregulated STAT5–TGF-β–STAT3 network contributes to the development of chronic liver disease.
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影响因子：
20.3
作者：
Hoelbl A;Kovacic B;Kerenyi MA;Simma O;Warsch W;Cui Y;Beug H;Hennighausen L;Moriggl R;Sexl V
通讯作者：
Sexl V
影响因子：
158.5
作者：
Kofoed, EM;Hwa, V;Rosenfeld, RG
通讯作者：
Rosenfeld, RG
影响因子：
2.6
作者：
Liu, Geqiang;Wang, Zhengqi;Bunting, Kevin D.
通讯作者：
Bunting, Kevin D.
影响因子：
56.9
作者：
Darnell, JE
通讯作者：
Darnell, JE
影响因子：
4.8
作者：
Kaimori, Aki;Potter, James;Koteish, Ayman
通讯作者：
Koteish, Ayman