Two distinct E3 ligases, SCF^FBXL19and HECW1, degrade thyroid transcription factor 1 in normal thyroid epithelial and follicular thyroid carcinoma cells, respectively

Abstract

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. FASEB J. 33, 10538–10550 (2019). http://www.fasebj.org

ETS1-activated SNHG10 exerts oncogenic functions in glioma via targeting miR-532-3p/FBXL19 axis

“…Our study found that FBXL19 was up-regulated in glioma cells, and down-regulating FBXL19 could restrict the growth and stemness of glioma cells. Although the precise downstream mechanism of FBXL19 in facilitating glioma development was not elucidated here, it functions as a ubiquitin E3 ligase to affect the ubiquitination and degradation of certain proteins has been disclosed by several reports [ 32 , 33 ]. Next, rescue experiments proved that FOXBL19 was required for the contribution of SNHG10 to gliomagenesis.…”

SCF FBXW17 E3 ubiquitin ligase regulates FBXL19 stability and cell migration

“…FBXL19 is a component of SCF FBXL19 E3 ligase complex. Its roles in inflammatory responses and regulation of small GTPases have been reported 17‐23 . Recent studies indicate that FBXL19 is not stable and its degradation is mediated by the ubiquitin–proteasome system 19,20 .…”

“…FBXL19 is a component of SCF FBXL19 E3 ligase, which has been shown to regulate inflammatory responses, cell proliferation, and migration 17‐23 . Multiple substrates have been identified for SCF FBXL19 E3 ligase including IL‐33 receptor and Rac1 17‐23 . In addition to identifying unrevealed substrates of SCF FBXL19 E3 ligase, recent studies have been focused on investigating molecular regulation of FBXL19 19,20 .…”

“…FBXL19 is a newly identified F‐box protein. FBXL19 targets multiple substrates and regulates various cellular functions including Rac1‐mediated cell migration 17‐23 . FBXL19 is localized in both the cytoplasm and nuclei.…”

Integrating HECW1 expression into the clinical indicators exhibits high accuracy in assessing the prognosis of patients with clear cell renal cell carcinoma

“…In addition, the novel mutant gene HECW1 was identified in muscle-invasive transitional cell carcinoma [ 11 ]. Moreover, HECW1 has been shown to degrade thyroid transcription factor 1 in follicular thyroid carcinoma cells [ 12 ]. However, the expression and prognostic significance of HECW1 in ccRCC is unknown.…”