Renal carcinoma-associated transcription factors TFE3 and TFEB are leukemia inhibitory factor-responsive transcription activators of E-cadherin.
Translocations of the genes encoding the related transcription factors TFE3 and TFEB are almost exclusively associated with a rare juvenile subset of renal cell carcinoma and lead to overexpression of TFE3 or TFEB protein sequences. A better understanding of how deregulated TFE3 and TFEB contribute to the transformation process requires elucidating more of the normal cellular processes in which they participate. Here we identify TFE3 and TFEB as cell type-specific leukemia inhibitory factor-responsive activators of E-cadherin. Overexpression of TFE3 or TFEB in 3T3 cells activated endogenous and reporter E-cadherin expression. Conversely, endogenous TFE3 and/or TFEB was required for endogenous E-cadherin expression in primary mouse embryonic fibroblasts and human embryonic kidney cells. Chromatin precipitation analyses and E-cadherin promoter reporter gene assays revealed that E-cadherin induction by TFE3 or TFEB was primarily or exclusively direct and mitogen-activated protein kinase-dependent in those cell types. In mouse embryonic fibroblasts, TFE3 and TFEB activation of E-cadherin was responsive to leukemia inhibitory factor. In 3T3 cells, TFE3 and TFEB expression also induced expression of Wilms' tumor-1, another E-cadherin activator. In contrast, E-cadherin expression in model mouse and canine renal epithelial cell lines was indifferent to inhibition of endogenous TFE3 and/or TFEB and was reduced by TFE3 or TFEB overexpression. These results reveal new cell type-specific activities of TFE3 and TFEB which may be affected by their mutation.
Department of Microbiology and Immunology and the Morse Institute for Molecular Genetics, State University of New York Downstate Medical Center, Brooklyn 11203, USA.
Chongmin
C
Huan
Deepa
D
Sashital
Tiruneh
T
Hailemariam
Matthew L
ML
Kelly
Christopher A J
CA
Roman
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D004285:Dogs; D004789:Enzyme Activation; D004847:Epithelial Cells; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D047468:Immunoprecipitation; D015850:Interleukin-6 / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007680:Kidney Neoplasms / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D025721:WT1 Proteins / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; D002843:Chromatin; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009363:Neoplasm Proteins; C069203:TFE3 protein, human; C064972:TFEB protein, human; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; D025721:WT1 Proteins; C068486:Tcfe3 protein, mouse; D008156:Luciferases