Renal Carcinoma-associated Transcription Factors TFE3 and TFEB Are Leukemia Inhibitory Factor-responsive Transcription Activators of E-cadherin

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 Ecadherin induction by TFE3 or TFEB was primarily or exclusively direct and mitogen-activated protein kinasedependent 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.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). The genetic lesions are translocations that lead to dramatic overexpression of TFE3 or TFEB protein sequences. Five different genetic loci have been identified as translocation partners for TFE3, which lead to the creation of a chimeric protein containing the translocation partner at the N terminus fused to the C-terminal portion of TFE3 which includes its DNA binding and multimerization domains (1). TFEB translocations result in promoter substitution and do not change the coding sequence (2, 3). Although there is evidence that TFE3 fusion partners contribute oncogenic properties to the fusion protein (4, 5), TFEB overexpression in RCC 1 and the ability of normal TFE3 to promote clonotypic growth of melanoma cells suggest that overexpression of the TFE3 protein sequence is a critical oncogenic force (2). Moreover, TFE3, and to a lesser extent, TFEB, have been implicated in several cytokine signaling pathways that control cell growth and differentiation, but the precise mechanisms by which their dysregulation contributes to renal oncogenesis are not clear.TFE3 and TFEB are closely related members of the Mi/TFE3 (MiT) transcription factor family that includes TFEC and the microphthalmia (mi) transcription factor Mitf (6). TFE3 or TFEB overexpress...

Leukemia inhibitory factor functions as a growth factor in pancreas carcinoma cells: Involvement of regulation of LIF and its receptor expression

“…Consistently, LIF activates STAT3 and enhances invasiveness by alteration of protease expression in choriocarcinoma cells (23). LIF has activated transcription factors, such as TRE3 and TFEB, which are activators of E-cadherin in renal carcinoma cells (24). LIF affects the promotion of carcinogenesis in a diverse range of carcinomas through activation of various transcription factors.…”

Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers

“…62,69-71 Importantly, either MiTF or TFE3 alone is sufficient to activate osteoclastogenesis, underscoring the phenomenon of functional redundancy within the MiT family, with one member able to rescue loss of another. 35,62,72,73 Certain MiT gene mutations may act as a “dominant negative” if they inhibit protein function but allow continued heterodimerization. Hence, MiTF mutations in the basic domain lead to osteoporosis in mice despite wild-type TFE3, presumably due to TFE3 sequestration in transcriptionally inactive heterodimers with the mutant MiTF protein.…”

“…85 TFE3 and TFEB additionally govern transcription of E-cadherin, an important regulator of cancer cell-cell interactions, as well as CD40L, the primary activator of T-cell lymphocytes, raising a possible role in tumor immunoevasion. 73,86 …”

Beyond indigestion: emerging roles for lysosome-based signaling in human disease

“…It remains to be determined how the cancer causing effects of excessive levels of MiT/TFE transcription factors relates to their roles as regulators of lysosome function. These transcription factors also have multiple targets with cancer relevance whose regulation by lysosome status remains unknown including: E-cadherin [83], a component of adherens junctions; CDK2, a kinase that regulates the cell cycle [84]; PGC1α, a transcriptional co-activator that regulates metabolism and mitochondrial function [85]; and Met, a receptor tyrosine kinase whose activating mutations are also common in renal carcinoma [77,86]. …”