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CDK5RAP3 is a co-factor for the oncogenic transcription factor STAT3.
Neoplasia ( IF 4.8 ) Pub Date : 2019-11-22 , DOI: 10.1016/j.neo.2019.10.002
Susana P Egusquiaguirre 1 , Suhu Liu 1 , Isidora Tošić 1 , Kevin Jiang 1 , Sarah R Walker 1 , Maria Nicolais 1 , Tzuen Yih Saw 1 , Michael Xiang 1 , Katarina Bartel 1 , Erik A Nelson 1 , David A Frank 1
Affiliation  

The transcription factor STAT3 regulates genes governing critical cellular processes such as proliferation, survival, and self-renewal. While STAT3 transcriptional function is activated rapidly and transiently in response to physiologic signals, through a variety of mechanisms it can become constitutively activated in the pathogenesis of cancer. This leads to chronic expression of genes that underlie malignant cellular behavior. However, STAT3 is known to interact with other proteins, which may modulate its function. Understanding these interactions can provide insights into novel aspects of STAT3 function and may also suggest strategies to therapeutically target the large number of cancers driven by constitutively activated STAT3. To identify critical modulators of STAT3 transcriptional function, we performed an RNA-interference based screen in a cell-based system that allows quantitative measurement of STAT3 activity. From this approach, we identified CDK5 kinase regulatory-subunit associated protein 3 (CDK5RAP3) as an enhancer of STAT3-dependent gene expression. We found that STAT3 transcriptional function is modulated by CDK5RAP3 in cancer cells, and silencing CDK5RAP3 reduces STAT3-mediated tumorigenic phenotypes including clonogenesis and migration. Mechanistically, CDK5RAP3 binds to STAT3-regulated genomic loci, in a STAT3-dependent manner. In primary human breast cancers, the expression of CDK5RAP3 expression was associated with STAT3 gene expression signatures as well as the expression of individual STAT3 target genes. These findings reveal a novel aspect of STAT3 transcriptional function and potentially provide both a biomarker of enhanced STAT3-dependent gene expression as well as a unique mechanism to therapeutically target STAT3.

中文翻译:

CDK5RAP3是致癌转录因子STAT3的辅助因子。

转录因子STAT3调节控制关键细胞过程(例如增殖,存活和自我更新)的基因。STAT3转录功能在响应生理信号后迅速而短暂地被激活,但通过多种机制它可以在癌症的发病机理中被组成性激活。这导致构成恶性细胞行为基础的基因的慢性表达。但是,已知STAT3与其他蛋白质相互作用,这可能会调节其功能。了解这些相互作用可以提供有关STAT3功能新方面的见解,也可以建议针对性治疗由STAT3组成性激活的大量癌症的治疗策略。为了确定STAT3转录功能的关键调节剂,我们在基于细胞的系统中进行了基于RNA干扰的筛查,该筛查能够定量测量STAT3的活性。通过这种方法,我们确定了CDK5激酶调节亚基相关蛋白3(CDK5RAP3)是STAT3依赖性基因表达的增强子。我们发现,STAT3转录功能受癌细胞中CDK5RAP3的调控,而沉默CDK5RAP3可减少STAT3介导的致瘤表型,包括克隆形成和迁移。从机理上讲,CDK5RAP3以STAT3依赖性方式与STAT3调控的基因组位点结合。在原发性人类乳腺癌中,CDK5RAP3的表达与STAT3基因的表达特征以及单个STAT3靶基因的表达相关。
更新日期:2019-11-22
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