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首页> 外文期刊>Cellular Signalling >Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS)
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Characterization of STAT5B phosphorylation correlating with expression of cytokine-inducible SH2-containing protein (CIS)

机译：STAT5B磷酸化的表征与细胞因子诱导的含SH2的蛋白（CIS）的表达相关

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摘要

Cytokine-inducible SH2-containing protein (CIS) is the first identified member of genes encoding for the suppressor of cytokine signaling (SOCS). CIS is also a well-known target gene of signal transducer and activator of transcription 5 (STAT5) pathways, providing normal negative feedback control of signaling by cytokines and growth factors. Three other SOCS genes, SOCS1, SOCS2, and SOCS3, can be silenced by DNA hypermethylation in human cancers, suggesting a potential mechanism for constitutive STAT activation. However, it is not known whether CIS expression is similarly perturbed in tumor cells. We report here the absence of CIS expression in T lymphoma LSTRA that overexpresses the Lek protein tyrosine kinase and exhibits elevated STAT5 activity. Pervanadate-induced CIS expression and STAT5 binding to the CIS promoter in vivo over a short time course implies that mechanisms other than DNA hypermethylation may contribute to defective CIS expression in LSTRA cells. Comparison with cytokine-dependent BaF3 cells stimulated with interleukin-3 (IL-3) further reveals that CIS induction correlates with specific STAT5b post-translational modifications. It exhibits as the slowest migrating form through SDS-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. This distinctly modified STAT5b is the predominant form that binds to the consensus STAT5 sites in the CIS promoter and accumulates in the nucleus. In vitro phosphatase assays and phosphoamino acid analysis suggest the involvement of phosphorylation on residues other than the highly conserved tyrosine and serine sites in this distinct STAT5b mobility shift. All together, our results provide a novel link between incomplete STAT5b phosphorylation and defective SOCS gene expression in cancer cells. (c) 2005 Elsevier Inc. All rights reserved.
机译：细胞因子诱导的含SH2的蛋白（CIS）是编码细胞因子信号转导（SOCS）抑制剂的基因的第一个鉴定成员。 CIS还是信号转导和转录激活子5（STAT5）通路的著名靶基因，可通过细胞因子和生长因子对信号进行正常的负反馈控制。 DNA甲基化可以使人类癌症中的其他三个SOCS基因SOCS1，SOCS2和SOCS3沉默，这提示STAT组成性激活的潜在机制。然而，尚不清楚在肿瘤细胞中CIS表达是否同样受到干扰。我们在这里报告的T淋巴瘤LSTRA中不存在CIS表达，该表达过度表达Lek蛋白酪氨酸激酶并表现出升高的STAT5活性。过氧钒酸盐诱导的CIS表达和STAT5在短时间内在体内与CIS启动子的结合暗示了DNA超甲基化以外的机制可能会导致LSTRA细胞中的CIS表达缺陷。与白介素3（IL-3）刺激的细胞因子依赖性BaF3细胞的比较进一步揭示了CIS诱导与特定STAT5b翻译后修饰相关。通过SDS-聚丙烯酰胺凝胶电泳（SDS-PAGE）分析，它表现为最慢的迁移形式。这种明显修饰的STAT5b是与CIS启动子中共有的STAT5位点结合并聚集在细胞核中的主要形式。体外磷酸酶测定和磷酸氨基酸分析表明，除了高度保守的酪氨酸和丝氨酸位点以外，残基中的磷酸化还参与了这种独特的STAT5b迁移。总之，我们的结果为癌细胞中不完全的STAT5b磷酸化与有缺陷的SOCS基因表达之间提供了新颖的联系。 （c）2005 Elsevier Inc.保留所有权利。

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