The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25A promoter
The STAT3 transcription factor is a target for the Myc and riboblastoma proteins on the Cdc25A promoter
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DOI：
10.1074/jbc.m413203200
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发表时间：
2005-04-22
影响因子：
4.8
通讯作者：
Coqueret, O
中科院分区：
文献类型：
--
作者：
Barré, B;Vigneron, A;Coqueret, O
STAT3 （signal transducer and activator of transcription）转录因子是生长因子信号传导的下游效应因子。STAT3的激活在正常细胞中是短暂的，但在一些癌细胞系和原发肿瘤中发现了这种转录因子的组成型激活形式。STAT3通过上调细胞周期和存活基因，在细胞生长、抗凋亡和细胞转化中发挥重要作用，但其分子基础尚不清楚。在这项研究中，我们发现STAT3及其转录辅助因子被招募到Cdc25A基因的启动子上，以激活其表达。利用染色质免疫沉淀法，我们观察到Myc在STAT3 DNA结合后被招募到这个启动子上。此外，小干扰rna介导的Myc敲低特异性抑制stat3介导的Cdc25A激活。Myc蛋白水平的降低导致creb结合蛋白、Cdk9和RNA聚合酶复合物的募集缺陷，表明Myc是STAT3转录所必需的。令人惊讶的是，STAT3与Cdc25A启动子的关联并不一定导致转录诱导，因为该蛋白也作为Cdc25A基因的转录抑制因子。过氧化氢刺激后，STAT3与视网膜母细胞瘤（Rb）肿瘤抑制因子形成抑制复合物，占据Cdc25A启动子并阻断其诱导。在共免疫沉淀和ChIP实验中，Rb被发现与DNA上的STAT3结合，我们提供了Rb直接结合转录因子的证据。因此，我们提出Myc和STAT3协同诱导Cdc25A的表达，并且它们的转录活性通常受Rb肿瘤抑制基因的调控。
The STAT3 ( signal transducer and activator of transcription) transcription factor functions as downstream effector of growth factor signaling. Whereas STAT3 activation is transient in normal cells, constitutively activated forms of the transcription factor have been detected in several cancer cell lines and primary tumors. Through the up-regulation of cell cycle and survival genes, STAT3 plays important roles in cell growth, anti-apoptosis, and cell transformation yet the molecular basis for this behavior is poorly understood. In this study, we show that STAT3 and its transcriptional cofactors are recruited to the promoter of the Cdc25A gene to activate its expression. Using chromatin immunoprecipitations, we observed that Myc is recruited to this promoter following STAT3 DNA binding. Moreover, small interfering RNA-mediated knockdown of Myc specifically inhibits the STAT3-mediated activation of Cdc25A. Reduction in Myc protein level results in defective recruitment of the CREB-binding protein, Cdk9, and RNA polymerase complexes, indicating that Myc is necessary for STAT3 transcription. Surprisingly, the association of STAT3 with the Cdc25A promoter does not necessarily lead to transcriptional induction because this protein also functions as a transcriptional repressor of the Cdc25A gene. Following hydrogen peroxide stimulation, STAT3 forms a repressor complex with the retinoblastoma (Rb) tumor suppressor to occupy the Cdc25A promoter and block its induction. In coimmunoprecipitations and ChIP experiments, Rb was found to associate with STAT3 on DNA and we provide evidence that Rb binds directly to the transcription factor. Thus, we propose that Myc and STAT3 cooperate to induce the expression of Cdc25A and that their transcriptional activity is normally regulated by the Rb tumor suppressor gene.