Mitochondrial translocation of signal transducer and activator of transcription 5 (STAT5) in leukemic T cells and cytokine-stimulated cells.
Mitochondrial translocation of signal transducer and activator of transcription 5 (STAT5) in leukemic T cells and cytokine-stimulated cells.
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DOI：
10.1016/j.bbrc.2010.10.112
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发表时间：
2010-11-26
影响因子：
3.1
通讯作者：
Yu CL
中科院分区：
文献类型：
--
作者：
Chueh FY;Leong KF;Yu CL
信号转导和转录激活因子（STAT）首先被确定为响应细胞因子的关键信号分子。组成性STAT激活也广泛涉及肿瘤发生。我们分析了STAT 5相关蛋白在白血病T细胞系LSTRA，表现出组成性酪氨酸磷酸化和激活STAT 5。通过免疫共沉淀发现一种细胞蛋白与LSTRA细胞中的STAT 5特异性相互作用。测序分析和随后的免疫印迹证实了这种STAT 5相关蛋白作为线粒体丙酮酸脱氢酶复合物（PDC-E2）的E2组分的身份。与这种相互作用相一致，亚细胞分级分离和免疫荧光显微镜显示LSTRA细胞中STAT 5的线粒体定位。酪氨酸磷酸化的STAT 5的线粒体定位也发生在精氨酸刺激的细胞中。时程实验进一步证明了细胞因子刺激后STAT 5线粒体易位的瞬时动力学。相反，精氨酸诱导的STAT 1和STAT 3激活并不导致它们易位到线粒体中。此外，我们发现，线粒体STAT 5结合的D-环调控区的线粒体DNA在体外。这表明STAT 5在调节线粒体基因组中的潜在作用。向有氧糖酵解的分解代谢在癌细胞中是众所周知的瓦尔堡效应，并且在奎宁刺激的细胞中也观察到。我们的新发现，精氨酸诱导的STAT 5易位到线粒体及其与肿瘤发生的联系提供了重要的见解，这种特征性的代谢转变的潜在机制。
Signal transducers and activators of transcription (STATs) were first identified as key signaling molecules in response to cytokines. Constitutive STAT activation also has been widely implicated in oncogenesis. We analyzed STAT5-associated proteins in a leukemic T cell line LSTRA, which exhibits constitutive tyrosine phosphorylation and activation of STAT5. A cellular protein was found to specifically interact with STAT5 in LSTRA cells by co-immunoprecipitation. Sequencing analysis and subsequent immunoblotting confirmed the identity of this STAT5-associated protein as the E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2). Consistent with this interaction, both subcellular fractionation and immunofluorescence microscopy revealed mitochondrial localization of STAT5 in LSTRA cells. Mitochondrial localization of tyrosine-phosphorylated STAT5 also occurred in cytokine-stimulated cells. A time course experiment further demonstrated the transient kinetics of STAT5 mitochondrial translocation after cytokine stimulation. In contrast, cytokine-induced STAT1 and STAT3 activation did not result in their translocation into mitochondria. Furthermore, we showed that mitochondrial STAT5 bound to the D-loop regulatory region of mitochondrial DNA in vitro. It suggests a potential role of STAT5 in regulating mitochondrial genome. Proliferative metabolism toward aerobic glycolysis is well known in cancer cells as the Warburg effect and is also observed in cytokine-stimulated cells. Our novel findings of cytokine-induced STAT5 translocation into mitochondria and its link to oncogenesis provide important insights into the underlying mechanisms of this characteristic metabolic shift.
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DOI：
10.1126/science.1164551
发表时间：
2009-02-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wegrzyn J;Potla R;Chwae YJ;Sepuri NB;Zhang Q;Koeck T;Derecka M;Szczepanek K;Szelag M;Gornicka A;Moh A;Moghaddas S;Chen Q;Bobbili S;Cichy J;Dulak J;Baker DP;Wolfman A;Stuehr D;Hassan MO;Fu XY;Avadhani N;Drake JI;Fawcett P;Lesnefsky EJ;Larner AC
通讯作者：
Larner AC
影响因子：
2.9
作者：
BLUM, H;BEIER, H;GROSS, HJ
通讯作者：
GROSS, HJ
影响因子：
3.6
作者：
Pieczenik, Steve R.;Neustadt, John
通讯作者：
Neustadt, John
影响因子：
7
作者：
Bogenhagen, DF;Wang, YS;Kobayashi, R
通讯作者：
Kobayashi, R
影响因子：
5.2
作者：
Shi, MJ;Cooper, JC;Yu, CL
通讯作者：
Yu, CL