التفاصيل البيبلوغرافية
| العنوان: |
Structure-Function Studies of the bHLH Phosphorylation Domain of TWIST1 in Prostate Cancer Cells. |
| المؤلفون: |
Gajula, Rajendra P.1, Chettiar, Sivarajan T.1, Williams, Russell D.1, Nugent, Katriana1, Kato, Yoshinori2,3,4, Wang, Hailun1, Malek, Reem1, Taparra, Kekoa1,5, Cades, Jessica1, Annadanam, Anvesh1, Yoon, A.-Rum6, Fertig, Elana7, Firulli, Beth A.8, Mazzacurati, Lucia8,9, Burns, Timothy F.8,9, Firulli, Anthony B.8, An, Steven S.4,6,10,11, Tran, Phuoc T.1,3,4,5,12 tranp@jhmi.edu |
| المصدر: |
Neoplasia. Jan2015, Vol. 17 Issue 1, p16-31. 16p. |
| مصطلحات موضوعية: |
*PROSTATE cancer & genetics, *PHOSPHORYLATION, *CANCER cells, *TRANSCRIPTION factors, *CANCER research |
| مستخلص: |
The TWIST1 gene has diverse roles in development and pathologic diseases such as cancer. TWIST1 is a dimeric basic helixloop-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 cancermetastasis. 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 tometastasis, 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-inducedmigration 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. [ABSTRACT FROM AUTHOR] |
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