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首页> 外文期刊>Neoplasia: an international journal for oncology research >Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells
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Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells

机译：前列腺癌细胞捻度1的BHLH磷酸化结构域的结构函数研究

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The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helix-loop-helix (bHLH) transcription factor existing as TWIST1-TWIST1 or TWIST1-E12/47. TWIST1 partner choice and DNA binding can be influenced during development by phosphorylation of Thr125 and Ser127 of the Thr-Gln-Ser (TQS) motif within the bHLH of TWIST1. The significance of these TWIST1 phosphorylation sites for metastasis is unknown. We created stable isogenic prostate cancer cell lines overexpressing TWIST1 wild-type, phospho-mutants, and tethered versions. We assessed these isogenic lines using assays that mimic stages of cancer metastasis. In vitro assays suggested the phospho-mimetic Twist1-DQD mutation could confer cellular properties associated with pro-metastatic behavior. The hypo-phosphorylation mimic Twist1-AQA mutation displayed reduced pro-metastatic activity compared to wild-type TWIST1 in vitro, suggesting that phosphorylation of the TWIST1 TQS motif was necessary for pro-metastatic functions. In vivo analysis demonstrates that the Twist1-AQA mutation exhibits reduced capacity to contribute to metastasis, whereas the expression of the Twist1-DQD mutation exhibits proficient metastatic potential. Tethered TWIST1-E12 heterodimers phenocopied the Twist1-DQD mutation for many in vitro assays, suggesting that TWIST1 phosphorylation may result in heterodimerization in prostate cancer cells. Lastly, the dual phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor BEZ235 strongly attenuated TWIST1-induced migration that was dependent on the TQS motif. TWIST1 TQS phosphorylation state determines the intensity of TWIST1-induced pro-metastatic ability in prostate cancer cells, which may be partly explained mechanistically by TWIST1 dimeric partner choice.
机译：Twist1基因在癌症如癌症如癌​​症和病理疾病中具有多种的作用。 Twist1是作为Twist1-Twist1或Twist1-E12 / 47的二聚体基本螺旋环 - 螺旋（BHLH）转录因子。 Twist1合作伙伴选择和DNA结合可以在开发过程中通过THR-GLN-SER（TQS）主题的磷酸化在TWICK1的BHLH内的磷酸化。这些Twist1磷酸化位点用于转移的重要性是未知的。我们创建了过表达Twist1野生型，磷酸突变体和系环形版本的稳定的等源前列腺癌细胞系。我们使用模拟癌症转移的阶段的测定评估这些中源性线。体外测定表明，磷酸磷模拟Twort1-DQD突变可以赋予与Pro-MetaTatic行为相关的细胞性质。与体外野生型Twist1相比，与野生型捻度相比显示出降低的磷酸化模拟活性，表明Pro-MetaTive功能是必需的。体内分析表明，Twist1-AQA突变表现出贡献转移的能力降低，而Twist1-DQD突变的表达表现出易于转移性潜力。束缚Twist1-E12异二聚体对许多体外测定的Twist1-DQD突变有影成，表明Twist1磷酸化可能导致前列腺癌细胞中的异二种化。最后，双磷脂酰亚肌酐3-激酶（PI3K） - 哺乳动物催化剂靶标（MTOR）抑制剂BEZ235依赖于TQS基序的偏移较强衰减的迁移。 Twist1 TQS磷酸化状态决定了前列腺癌细胞中Twist1诱导的Pro-MetaTatic能力的强度，其可以通过Twist1二聚体合作伙伴选择将其机械地解释。

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