Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation
Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation
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DOI：
10.1128/mcb.24.8.3227-3237.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Mitani, K
中科院分区：
文献类型：
--
作者：
Maki, K;Arai, H;Mitani, K
TEL是ETS家族转录因子，具有多个推定的促分裂原活化蛋白激酶磷酸化位点。在这里，我们描述了通过ERK途径的TEL的功能调节。过表达的TEL在体内被活化的ERK磷酸化。TEL也在体外被ERK直接磷酸化。可诱导的磷酸化位点是Ser（213）和Ser（257）。TEL与ERK中的共同对接结构域结合。体内ERK依赖性磷酸化降低了TEL对ETS结合位点的反式抑制和DNA结合能力。在Ser（213）和Ser（257）上携带取代的谷氨酸的突变体在功能上模拟过度磷酸化的TEL，并且还显示对TEL诱导的转录抑制的显性负效应。通过磷酸化失去DNA结合亲和力，但与未修饰的TEL异二聚化可能是一个潜在的机制。此外，谷氨酸突变体主要干扰MEL细胞中TEL诱导的红系分化和NIH 3T3细胞中的生长抑制。最后，内源性TEL在分化的MEL细胞中与ERK失活平行地去磷酸化，并且在Ras转化的NIH 3T3细胞中通过ERK活化而磷酸化。这些结果表明，在信号转导系统中，TEL是ERK的下游成分，在分子和生物学特性上受ERK的生理调节。
TEL is an ETS family transcription factor that possesses multiple putative mitogen-activated protein kinase phosphorylation sites. We here describe the functional regulation of TEL via ERK pathways. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). TEL binds to a common docking domain in ERK. In vivo ERK-dependent phosphorylation reduces trans-repressional and DNA-binding abilities of TEL for ETS-binding sites. A mutant carrying substituted glutamates on both Ser(213) and Ser(257) functionally mimics hyperphosphorylated TEL and also shows a dominant-negative effect on TEL-induced transcriptional suppression. Losing DNA-binding affinity through phosphorylation but heterodimerizing with unmodified TEL could be an underlying mechanism. Moreover, the glutamate mutant dominantly interferes with TEL-induced erythroid differentiation in MEL cells and growth suppression in NIH 3T3 cells. Finally, endogenous TEL is dephosphorylated in parallel with ERK inactivation in differentiating MEL cells and is phosphorylated through ERK activation in Ras-transformed NIH 3T3 cells. These data indicate that TEL is a constituent downstream of ERK in signal transduction systems and is physiologically regulated by ERK in molecular and biological features.