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Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells12

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العنوان:	Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells12
المؤلفون:	Gajula, Rajendra P., Chettiar, Sivarajan T., Williams, Russell D., Nugent, Katriana, Kato, Yoshinori, Wang, Hailun, Malek, Reem, Taparra, Kekoa, Cades, Jessica, Annadanam, Anvesh, Yoon, A-Rum, Fertig, Elana, Firulli, Beth A., Mazzacurati, Lucia, Burns, Timothy F., Firulli, Anthony B., An, Steven S., Tran, Phuoc T.
المصدر:	Neoplasia (New York, N.Y.)
بيانات النشر:	Neoplasia Press, 2015.
سنة النشر:	2015
مصطلحات موضوعية:	Male, animal structures, Epithelial-Mesenchymal Transition, Amino Acid Motifs, Article, PI, propidium iodide, Phosphatidylinositol 3-Kinases, Structure-Activity Relationship, bHLH, basic helix-loop-helix, Cell Movement, T-E, TWIST1-E12, Cell Line, Tumor, Basic Helix-Loop-Helix Transcription Factors, Animals, Cluster Analysis, Humans, Protein Interaction Domains and Motifs, Neoplasm Metastasis, Phosphorylation, Protein Kinase Inhibitors, Gene Expression Profiling, TOR Serine-Threonine Kinases, Twist-Related Protein 1, T-T, TWIST1-TWIST1, Nuclear Proteins, Prostatic Neoplasms, Disease Models, Animal, Mutation, Heterografts, PKA, protein kinase A, E12/E47, E2A proteins, Protein Multimerization, EMT, epithelial-mesenchymal transition, Transcriptome, Proto-Oncogene Proteins c-akt, IHC, immunohistochemistry, Signal Transduction
الوصف:	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.
اللغة:	English
تدمد:	1476-5586 1522-8002
الوصول الحر:	https://explore.openaire.eu/search/publication?articleId=pmid________::7f92faa209cec62bb68d85091e492170Test http://europepmc.org/articles/PMC4309734Test
حقوق:	OPEN
رقم الانضمام:	edsair.pmid..........7f92faa209cec62bb68d85091e492170
قاعدة البيانات:	OpenAIRE

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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. 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