Suppression of STAT3 activity by Duplin, which is a negative regulator of the Wnt signal.
Suppression of STAT3 activity by Duplin, which is a negative regulator of the Wnt signal.
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DOI：
10.1093/jb/mvj033
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发表时间：
2006-02
影响因子：
2.7
通讯作者：
K. Yamashina;Hideki Yamamoto;K. Chayama;K. Nakajima;A. Kikuchi
中科院分区：
文献类型：
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作者：
K. Yamashina;Hideki Yamamoto;K. Chayama;K. Nakajima;A. Kikuchi
Duplin最初是作为Wnt信号通路中β-连环蛋白依赖性T细胞因子(Tcf)转录活性的负调节因子而被分离出来的。然而，Duplin基因敲除的小鼠在5.5-em天表现出胚胎致死性，这表明Duplin除了作为Wnt信号的负调控外，还有其他重要的作用。为了确定Duplin的新功能，我们筛选了Duplin结合蛋白。PIAS3是一种相扑E3连接酶，是信号转导和转录激活因子(STAT3)的抑制因子，是一种双倍体结合蛋白。Duplin被Sumoyl化，但PIAS3既不影响Duplin的Sumoyl化，也不影响其抑制Tcf-4活性的能力。与PIAS3一样，Duplin抑制白血病抑制因子(LIF)诱导的STAT3转录活性。Duplin不影响依赖LIF的STAT3的酪氨酸磷酸化或核定位，但抑制STAT3与DNA的复合体的形成。虽然STAT3没有被相扑修饰，但PIAS3抑制STAT3活性的方式部分依赖于其相扑E3连接酶的活性。Duplin抑制依赖LIF的STAT3活性，而不依赖于SUMO。这些结果表明，Duplin不仅抑制Tcf-4，而且还抑制STAT3，提示Duplin可能是多种转录因子的抑制物。
Duplin was originally isolated as a negative regulator of beta-catenin-dependent T-cell factor (Tcf) transcriptional activity in the Wnt signaling pathway. However, Duplin knockout mice exhibit embryonic lethality at 5.5-em day, suggesting that Duplin has important roles other than as a negative regulator of the Wnt signal. To identify new roles of Duplin, the Duplin-binding proteins were screened. PIAS3, which is a SUMO E3 ligase and acts as an inhibitor of signal transducer and activator of transcription (STAT3), was identified as a Duplin-binding protein. Duplin was sumoylated, but PIAS3 affected neither the sumoylation of Duplin nor its ability to inhibit Tcf-4 activity. Like PIAS3, Duplin suppressed the leukemia-inhibitory factor (LIF)-induced STAT3 transcriptional activity. Duplin did not affect the LIF-dependent tyrosine phosphorylation or nuclear localization of STAT3 but inhibited the formation of complex between STAT3 and DNA. Although STAT3 is not modified with SUMO, PIAS3 inhibited the STAT3 activity in a manner partially depending on its SUMO E3 ligase activity. Duplin suppressed the LIF-dependent STAT3 activity independently of sumoylation. These results demonstrate that Duplin inhibits not only Tcf-4 but also STAT3, suggesting that Duplin may act as a repressor for multiple transcriptional factors.