The prolyl isomerase pin1 regulates mRNA levels of genes with short half-lives by targeting specific RNA binding proteins.
The prolyl isomerase pin1 regulates mRNA levels of genes with short half-lives by targeting specific RNA binding proteins.
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DOI：
10.1371/journal.pone.0085427
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Thapar R
中科院分区：
文献类型：
--
作者：
Krishnan N;Titus MA;Thapar R
肽基脯氨酰异构酶Pin 1在几种癌症组织中过表达，是前列腺癌的潜在预后标志物，Pin 1消融可以抑制乳腺癌和前列腺癌的肿瘤发生。Pin 1可以与激活的ErbB 2或Ras协同作用，以增强肿瘤发生。它通过调节基因表达和细胞增殖所必需的蛋白质的活性来实现这一点。Pin 1的几个靶点，如c-Myc、雄激素受体、雌激素受体-α、细胞周期蛋白D1、细胞周期蛋白E、p53、RAF激酶和NCOA 3在癌症中失调。在转录后水平，新的证据表明Pin 1还通过分别与组蛋白mRNA特异性蛋白SLBP和ARE结合蛋白AUF 1和KSRP相互作用来调节组蛋白mRNA、GM-CSF、Pth和TGFβ mRNA的mRNA衰变。为了了解Pin 1如何在哺乳动物细胞中影响全基因组范围内的mRNA丰度，我们使用RNAi沿着DNA微阵列来鉴定响应Pin 1敲低而丰度显著改变的基因。差异表达基因的功能评分显示Pin 1基因靶点控制细胞粘附、白细胞迁移、磷脂酰肌醇信号系统和DNA复制。Pin 1基因敲除后，一些mRNA的丰度发生了显著变化，这些mRNA的3′非翻译区含有富含AU的元件（ARE）序列。我们确定HuR和AUF 1作为Pin 1相互作用ARE结合蛋白在体内。在这项研究中还发现Pin 1稳定了所有核心组蛋白mRNA，从而验证了我们先前发表的研究结果。统计分析表明，Pin 1可能靶向本质上不稳定且具有短至中等半衰期的必需mRNA的衰变。因此，这项研究表明，Pin 1的一个重要生物学作用是通过与可能在癌症进展中发挥作用的特定RNA结合蛋白相互作用来调节mRNA的丰度和稳定性。
The peptidyl-prolyl isomerase Pin1 is over-expressed in several cancer tissues is a potential prognostic marker in prostate cancer, and Pin1 ablation can suppress tumorigenesis in breast and prostate cancers. Pin1 can co-operate with activated ErbB2 or Ras to enhance tumorigenesis. It does so by regulating the activity of proteins that are essential for gene expression and cell proliferation. Several targets of Pin1 such as c-Myc, the Androgen Receptor, Estrogen Receptor-alpha, Cyclin D1, Cyclin E, p53, RAF kinase and NCOA3 are deregulated in cancer. At the posttranscriptional level, emerging evidence indicates that Pin1 also regulates mRNA decay of histone mRNAs, GM-CSF, Pth, and TGFβ mRNAs by interacting with the histone mRNA specific protein SLBP, and the ARE-binding proteins AUF1 and KSRP, respectively. To understand how Pin1 may affect mRNA abundance on a genome-wide scale in mammalian cells, we used RNAi along with DNA microarrays to identify genes whose abundance is significantly altered in response to a Pin1 knockdown. Functional scoring of differentially expressed genes showed that Pin1 gene targets control cell adhesion, leukocyte migration, the phosphatidylinositol signaling system and DNA replication. Several mRNAs whose abundance was significantly altered by Pin1 knockdown contained AU-rich element (ARE) sequences in their 3′ untranslated regions. We identified HuR and AUF1 as Pin1 interacting ARE-binding proteins in vivo. Pin1 was also found to stabilize all core histone mRNAs in this study, thereby validating our results from a previously published study. Statistical analysis suggests that Pin1 may target the decay of essential mRNAs that are inherently unstable and have short to medium half-lives. Thus, this study shows that an important biological role of Pin1 is to regulate mRNA abundance and stability by interacting with specific RNA-binding proteins that may play a role in cancer progression.
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