The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species-generating enzyme NOX4 and the proapoptotic proteins PUMA and BIM in mice.
The liver-specific tumor suppressor STAT5 controls expression of the reactive oxygen species-generating enzyme NOX4 and the proapoptotic proteins PUMA and BIM in mice.
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DOI：
10.1002/hep.25900
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发表时间：
2012-12
期刊：
影响因子：
13.5
通讯作者：
Hennighausen, Lothar
中科院分区：
文献类型：
--
作者：
Yu, Ji Hoon;Zhu, Bing-Mei;Riedlinger, Gregory;Kang, Keunsoo;Hennighausen, Lothar
肝组织中STAT5的缺失会导致肝脏骨质疏松症和促进细胞增殖。这项研究现在证明，肝脏特异的Stat5基因缺失的小鼠在17个月大时会患上严重的肝骨病和肝细胞癌，即使在没有化学侮辱的情况下也是如此。为了了解STAT5‘S作为肿瘤抑制因子的作用，我们发现并研究了新的STAT5靶基因。活性氧产生酶NOX4的编码基因NOX4是由生长激素通过STAT5诱导表达的。此外，编码促凋亡蛋白PUMA和BIM的基因是由生长激素通过STAT5诱导的，它们都与这三个基因启动子区域的GAS基序结合。我们进一步证明，STAT5诱导的彪马和Bim的激活依赖于NOX4。用细胞凋亡诱导剂转化生长因子-β处理小鼠，对照组小鼠的caspase3被切割，而肝脏特异的Stat5基因缺失的小鼠则没有。这项研究首次证明了细胞因子通过STAT5调节ROS生成酶NOX4和关键的促凋亡蛋白的表达。我们认为，STAT5在肝脏中利用了几个不同的信号通路，从而发挥了肿瘤抑制作用。除了抑制STAT3的激活外，STAT5还诱导促凋亡基因的表达和ROS的产生。
Loss of STAT5 from liver tissue results in hepatosteatosis and enhanced cell proliferation. This study now demonstrates that liver-specific Stat5-null mice develop severe hepatosteatosis as well as hepatocellular carcinomas at 17 months of age even in the absence of chemical insults. To understand STAT5’s role as tumor suppressor we have identified and investigated new STAT5 target genes. Expression of Nox4, the gene encoding the Reactive Oxygen Species (ROS) generating enzyme NOX4, was induced by growth hormone through STAT5. In addition, the genes encoding the pro-apoptotic proteins PUMA and BIM were induced by growth hormone through STAT5, which bound to GAS motifs in the promoter regions of all three genes. We further show that STAT5-induced activation of Puma and Bim was dependent on NOX4. Treatment of mice with TGF-β, an inducer of apoptosis, resulted in cleaved caspase 3 in control but not in liver-specific Stat5-null mice. This study for the first time demonstrates that cytokines through STAT5 regulate the expression of the ROS generating enzyme NOX4 and key pro-apoptotic proteins. We propose that STAT5 harnesses several distinct signaling pathways in liver and thereby functions as a tumor suppressor. Besides suppressing the activation of STAT3, STAT5 induces the expression of pro-apoptotic genes and the production of ROS.
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影响因子：
11.2
作者：
Qiu, Wei;Carson-Walter, Eleanor B.;Yu, Jian
通讯作者：
Yu, Jian
影响因子：
25.7
作者：
Akazawa Y;Cazanave S;Mott JL;Elmi N;Bronk SF;Kohno S;Charlton MR;Gores GJ
通讯作者：
Gores GJ
DOI：
10.1073/pnas.1002178107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
通讯作者：
Sadoshima, Junichi
影响因子：
32.4
作者：
Kaufmann, Thomas;Jost, Philipp J.;Pellegrini, Marc;Puthalakath, Hamsa;Gugasyan, Raffi;Gerondakis, Steve;Cretney, Erika;Smyth, Mark J.;Silke, John;Hakem, Razq;Bouillet, Philippe;Mak, Tak W.;Dixit, Vishva M.;Strasser, Andreas
通讯作者：
Strasser, Andreas
影响因子：
13.5
作者：
Friedbichler, Katrin;Themanns, Madeleine;Moriggl, Richard
通讯作者：
Moriggl, Richard