Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thyroid transcription factor 1 (TTF1/NKX2.1), is a nuclear protein member of the NKX2 family of homeodomain transcription factors. It plays a critical role in regulation of multiple organ functions by promoting gene expression, such as thyroid hormone in thyroid and surfactant proteins in the lung. However, molecular regulation of TTF1 has not been well investigated, especially regarding its protein degradation. Here we show that protein kinase C agonist, phorbol esters (PMA), reduces TTF1 protein levels in time- and dose-dependent manners, without altering TTF1 mRNA levels. TTF1 is ubiquitinated and degraded in the proteasome in response to PMA, suggesting that PMA induces TTF1 degradation in the ubiquitin-proteasome system. Furthermore, we demonstrate that an E3 ubiquitin ligase, named HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 (HECW1), targets TTF1 for its ubiquitination and degradation, while downregulation of HECW1 attenuates PMA-induced TTF1 ubiquitination and degradation. A lysine residue lys151 was identified as the ubiquitin acceptor site within the TTF1. A lys151 to arginine mutant of TTF1 (TTF1K151R) is resistant to PMA- or HECW1-mediated ubiquitination and degradation. Further, we reveal that overexpression of TTF1 increases lung epithelial cell migration and proliferation, while the effects are reversed by HECW1. This study is the first to demonstrate that the E3 ubiquitin ligase HECW1 regulates TTF1 degradation by site-specific ubiquitination. This study will provide a new direction to clarify the molecular regulation of TTF1 in lung and its role in lung epithelial remodeling after injury.
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PMID:The E3 ubiquitin ligase HECW1 targets thyroid transcription factor 1 (TTF1/NKX2.1) for its degradation in the ubiquitin-proteasome system. 3084 19

Thyroid transcription factor 1 (TTF1) regulates the tissue-specific expression of genes. However, the molecular regulation of TTF1 in thyroid normal and carcinoma cells has not been revealed. Here we identify 2 distinct ubiquitin E3 ligases that are responsible for TTF1 degradation in normal thyroid cells and carcinoma cells, respectively. Phorbol myristate acetate induced TTF1 protein degradation in the ubiquitin-proteasome system in both HTori3 thyroid follicular epithelial cells and follicular thyroid carcinoma 133 (FTC133) cells. Lysine 151 residue was identified as a ubiquitin acceptor site within TTF1 in both cell types. Overexpression of E3 ubiquitin protein ligase 1 containing HECT, C2, and WW domain (HECW1) induced TTF1 degradation and ubiquitination in Htori3 cells but not in FTC133 cells. Overexpression of ubiquitin E3 ligase subunit FBXL19 increased TTF1 ubiquitination and degradation in FTC133 cells, but it had no effect on TTF1 levels in Htori3 cells. Overexpression of TTF1 increased thyroglobulin and sodium/iodide symporter mRNA levels, cell migration, and proliferation in HTori3 cells, whereas the effects were reversed by the overexpression of HECW1. This study reveals an undiscovered molecular mechanism by which TTF1 ubiquitination and degradation is regulated by different E3 ligases in thyroid normal and tumor cells.-Liu, J., Dong, S., Wang, H., Li, L., Ye, Q., Li, Y., Miao, J., Jhiang, S., Zhao, J., Zhao, Y. Two distinct E3 ligases, SCFFBXL19 and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively.
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PMID:Two distinct E3 ligases, SCFFBXL19 and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively. 3123 8