Pin1 Regulates the Dynamics of c-Myc DNA Binding To Facilitate Target Gene Regulation and Oncogenesis
Pin1 Regulates the Dynamics of c-Myc DNA Binding To Facilitate Target Gene Regulation and Oncogenesis
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DOI：
10.1128/mcb.01455-12
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发表时间：
2013-08-01
影响因子：
5.3
通讯作者：
Sears, Rosalie C.
中科院分区：
文献类型：
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作者：
Farrell, Amy S.;Pelz, Carl;Sears, Rosalie C.
由于Myc癌蛋白能够调节大部分基因的表达，因此被认为是基因转录的主要调控因子。然而，指导Myc募集到DNA和靶基因选择以引发特定细胞功能的机制尚未得到很好的阐明。在这里，我们报道了Pin1脯氨酸异构酶在基因激活过程中增强丝氨酸62磷酸化Myc及其共激活因子的募集，从而选择启动子，随后促进Myc的释放并与其降解相关。这有助于Myc激活参与细胞生长和代谢的基因，从而在控制Myc水平的同时增强促增殖活性。在Myc降解受损的癌细胞中，尽管Pin1不再促进Myc降解，但它仍然增强Myc DNA结合。因此，我们发现Pin1和Myc在癌症中过度表达，这驱动了一种基因表达模式，我们发现这种表达模式在预后较差的乳腺癌亚型中富集。本研究为研究Myc DNA结合和致癌活性的调控机制提供了新的视角，揭示了Pin1在调控转录因子中的新作用，并阐明了Pin1与Myc协同致癌的机制。
The Myc oncoprotein is considered a master regulator of gene transcription by virtue of its ability to modulate the expression of a large percentage of all genes. However, mechanisms that direct Myc's recruitment to DNA and target gene selection to elicit specific cellular functions have not been well elucidated. Here, we report that the Pin1 prolyl isomerase enhances recruitment of serine 62-phosphorylated Myc and its coactivators to select promoters during gene activation, followed by promoting Myc's release associated with its degradation. This facilitates Myc's activation of genes involved in cell growth and metabolism, resulting in enhanced proproliferative activity, even while controlling Myc levels. In cancer cells with impaired Myc degradation, Pin1 still enhances Myc DNA binding, although it no longer facilitates Myc degradation. Thus, we find that Pin1 and Myc are cooverexpressed in cancer, and this drives a gene expression pattern that we show is enriched in poor-outcome breast cancer subtypes. This study provides new insight into mechanisms regulating Myc DNA binding and oncogenic activity, it reveals a novel role for Pin1 in the regulation of transcription factors, and it elucidates a mechanism that can contribute to oncogenic cooperation between Pin1 and Myc.