Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis.
Signal transducer and activator of transcription 5b drives malignant progression in a PDGFB-dependent proneural glioma model by suppressing apoptosis.
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DOI：
10.1002/ijc.29264
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发表时间：
2015-05-01
影响因子：
6.4
通讯作者：
Rao, Ganesh
中科院分区：
文献类型：
--
作者：
Gressot, Loyola V.;Doucette, Tiffany A.;Yang, Yuhui;Fuller, Gregory N.;Heimberger, Amy B.;Boegler, Oliver;Rao, Arvind;Latha, Khatri;Rao, Ganesh
信号转导子和转录激活子5 b（STAT 5 b）可能是与胶质瘤恶性进展过程相关的STAT 5亚型。STAT 5 b是一种潜在的细胞质蛋白，通过调节生长因子、凋亡和血管生成参与细胞信号传导。先前的体外研究表明，相对于低级别肿瘤和正常大脑，成胶质细胞瘤中的STAT 5 b表达增加。我们最近证明，磷酸化STAT 5 b与细胞核中的δ表皮生长因子受体相关，随后结合下游效应分子的启动子，包括极光激酶A。TCGA数据集的分析显示，STAT 5 b主要在前神经（PN）胶质瘤中表达，相对于间充质和神经胶质瘤。在这里，我们模拟异位表达的STAT 5 B在体内使用血小板衍生生长因子亚基B（PDGFB）依赖性小鼠模型的PN胶质瘤，以确定其对肿瘤的形成和发展的影响。我们发现，STAT 5 b和PDGFB在小鼠中的共表达产生了比PDGFB单独表达显著更高的高级别胶质瘤率。我们还观察到联合表达组的生存期较短。来自STAT 5 b +PDGFB表达组的高级别肿瘤被发现具有比来自单独的PDGFB的高级别肿瘤更低的细胞凋亡率。此外，我们发现，与PDGFB单独来源的肿瘤相比，STAT 5 b +PDGFB的表达增加导致下游STAT 5 b靶点的表达增加，包括高级别肿瘤中的Bcl-xL、细胞周期蛋白D1和极光激酶A。我们的研究结果表明，STAT 5 b促进胶质瘤的恶性转化，特别是PN亚型，是一个潜在的治疗靶点。
Signal transducer and activator of transcription 5b (STAT5b) is likely the relevant STAT5 isoform with respect to the process of malignant progression in gliomas. STAT5b is a latent cytoplasmic protein involved in cell signaling through the modulation of growth factors, apoptosis, and angiogenesis. Previous in vitro studies have shown increased STAT5b expression in glioblastomas relative to low-grade tumors and normal brain. We recently demonstrated that phosphorylated STAT5b associates with delta epidermal growth factor receptor in the nucleus and subsequently binds the promoters of downstream effector molecules, including aurora kinase A. Analysis of TCGA dataset reveals that STAT5b is predominantly expressed in proneural (PN) gliomas relative to mesenchymal and neural gliomas. Here, we modeled ectopic expression of STAT5b in vivo using a platelet-derived growth factor subunit B (PDGFB)-dependent mouse model of PN glioma to determine its effect on tumor formation and progression. We showed that co-expression of STAT5b and PDGFB in mice yielded a significantly higher rate of high-grade gliomas than PDGFB expression alone. We also observed shorter survival in the combined expression set. High-grade tumors from the STAT5b+PDGFB expression set were found to have a lower rate of apoptosis than those from PDGFB alone. Furthermore, we showed that increased expression of STAT5b+PDGFB led to increased expression of downstream STAT5b targets, including Bcl-xL, cyclin D1, and aurora kinase A in high-grade tumors when compared to tumors derived from PDGFB alone. Our findings show that STAT5b promotes the malignant transformation of gliomas, particularly the PN subtype, and is a potential therapeutic target.
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影响因子：
3.7
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
通讯作者：
Holland E
影响因子：
4.3
作者：
Lehman, Norman L.;O'Donnell, James P.;Poisson, Laila M.
通讯作者：
Poisson, Laila M.
影响因子：
10.5
作者：
Dai, C;Celestino, JC;Holland, EC
通讯作者：
Holland, EC
DOI：
10.1006/mcbr.2000.0231
发表时间：
2000-05-01
期刊：
Molecular Cell Biology Research Communications
影响因子：
--
作者：
de Groot, Rolf P.;Raaijmakers, Jan A. M.;Koenderman, Leo
通讯作者：
Koenderman, Leo
影响因子：
15.9
作者：
Bromberg, J
通讯作者：
Bromberg, J