Transforming growth factor-£] (TGF-£])-activated kinase 1(TAK1), a member of the MAPKKK family, was identified as a protein kinase that involved in c-Jun N-terminal kinase(JNK)/p38 MAPKs and NF-£eB signaling pathways. This kinase also participated in inflammatory and innate immune responses as well as the aggressiveness in several types of cancer. Association with its specific activator protein, TAK1 binding protein1 (TAB1), triggers TAK1 kinase activity. Recent evidences suggest that the interaction between chemokines and their cognate receptors involved in cancer metastasis. Our previous results demonstrated that CC chemokine receptor 7 (CCR7), the receptor for the two major chemokines CCL19 and CCL21, is up-regulated in breast cancer cells and may play an important role in the trafficking and homing of breast cancer cells to lymph nodes. In addition, CCR7 expression is positively correlated with lymphatic metastasis in the primary tumors of patients with breast cancer. Here, we show that TAK1 is constitutively activated in MDA-MB-231 breast cancer cells and suppression of TAK1 signaling by using TAK1 shRNA or TAB1 shRNA significantly reduces expression of CCR7 in these cells. In addition, the TAK1 inhibitor 5Z-7-oxozeaenol, a resorcylic lactone of fungal origin, also inhibited TAK1 kinase activity and CCR7 expression. Promoter deletion assay identified a responsive element localized between -500/-223 bp from transcription start site is critical for TAK1 to activate CCR7 transcription. Furthermore, Chromatin immunoprecipitation assay(ChIP assay)identified two transcription factors, c-Jun and NF£eB participate in TAK1 regulating CCR7 expression. In addition, our study in breast tumor tissues indicated that CCR7 was significantly associated with p-TAK1 expression as found in breast cancer cell lines.
| Identifer | oai:union.ndltd.org:NSYSU/oai:NSYSU:etd-0816110-154704 |
| Date | 16 August 2010 |
| Creators | Huang, Huei-Lin |
| Contributors | Long-Sen Chang, Wen-Chun Hung, Yow-Ling Shiue |
| Publisher | NSYSU |
| Source Sets | NSYSU Electronic Thesis and Dissertation Archive |
| Language | Cholon |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0816110-154704 |
| Rights | restricted, Copyright information available at source archive |
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