Abstract
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.
Highlights
Deregulated expression of the related transcription factors TFE3 and TFEB is associated with rare, juvenile forms of the malignancy renal cell carcinoma (RCC), and TFE3 mutation with alveolar soft part sarcoma
TFE3 and TFEB Activate E-cadherin Expression in 3T3 Cells—To understand better normal TFE3 and TFEB function and how their deregulated expression could contribute to malignancy, we sought to identify new cellular processes and target genes regulated by both TFE3 and TFEB in different cell types
Our data support the existence of a new, cell type-specific receptor-target gene signaling pathway in which TFE3 and TFEB are direct, leukemia inhibitory factor (LIF)-responsive, and MAPK-dependent activators of E-cadherin
Summary
Deregulated expression of the related transcription factors TFE3 and TFEB is associated with rare, juvenile forms of the malignancy renal cell carcinoma (RCC), and TFE3 mutation with alveolar soft part sarcoma (for review, see Ref. 1). TFE3 or TFEB overexpression is predicted to sabotage proper regulation of MiT family target genes that control normal growth and differentiation. As an essential transcriptional effector of the c-Kit pathway, Mitf is critical for mast cell and melanocyte development (8 –10). Mitf expression can be deregulated in melanoma [11], and its ectopic overexpression in fibroblasts activates melanocyte-specific genes [12]. Consistent with the prediction, tumors overexpressing TFEB or a subset of TFE3 fusion proteins express some melanocyte markers [1, 2], which may be a reflection of known functional similarities. TFE3, like Mitf, can synergize with the Wnt transcriptional effector LEF-1 to activate melanocyte-specific promoters [13], and overexpression of Mitf or TFE3 rescues growth of melanoma cells in which. Several potentially important target genes and growth regulatory pathways could be affected by deregulated TFE3 activity
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