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Roman, Christopher AG
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Spring 2006
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2006-04-21
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Doctoral Dissertation
Adobe PDF, 2.82 MB
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TFE3 and TFEB are two closely related transcription factors belonging to the family of basic helix-loop-helix zipper (bHLH-Zip) transcription factors. TFE3 and TFEB regulate gene expression by forming dimers that bind to E3 sites in target gene promoters and/or enhancers. Some evidence suggests that TFE3 and TFEB have multiple common target genes in various types of cells and tissues, which reflects their sequence and distribution similarity. Moreover, translocations of TFE3 and TFEB genes that lead
to over-expression are associated with rare types of renal cell carcinoma. However, the physiological target genes of TFE3 and TFEB in vivo, and how mutations of TFE3 and TFEB genes cause cancers are largely unknown.
In the first set of my thesis studies, I found that TFE3 and TFEB might be functionally important for kidney development by regulating the transcription of Ecadherin, an epithelial marker, in response to the signals of leukemia inhibitory factor (LIF), an established mesenchymal to epithelial transition (MET) inducer in kidney development. This conclusion was based on following experiment results: over expression of TFE3 or TFEB induced E-cadherin and WT1 expression in transformed mesenchymal cells, and inhibiting both endogenous TFE3 and TFEB with RNA interference (RNAi) or a trans-dominant negative (TDN) protein inhibited E-cadherin expression in primary mesenchymal cells. In addition, TFE3 and TFEB were LIF responsive transcription activators of E-cadherin via the MAPK pathway in primary mesenchymal cells. Surprisingly, our data also showed that over- expressed TFE3 and TFEB partially inhibited E-cadherin expression in renal epithelial cells. Given the knowledge that down regulation of E-cadherin is associated with cancer progression and metastasis, this result implies that over expressed TFE3 and TFEB may contribute to renal malignancy by dysregulating tumor repressor genes’ expression, and gives new insight into etiology of the renal cancer.
In the remainder of the thesis studies, I also found an important in vivo function of TFE3 and TFEB in the immune system via regulating the expression of CD40 ligand (CD40L), a critical mediator of thymus (T)-dependent immune responses that is mainly
expressed by CD4 T cells, based on following experimental results: chromatin immunoprecipitation (ChIP) and reporter gene assays showed that both TFE3 and TFEB bound to the CD40L promoter and activated CD40L transcription in CD4 T cells, whereas
knocking down TFEB in TFE3-deficient T cells via RNAi impaired CD40L expression. Moreover, inhibition of TFE3 and TFEB simultaneously in T cells with the TDN protein via transgenesis resulted in a phenotype similar to X-linked hyper-IgM syndrome
(HIGM), a human disease caused by loss-of-function mutations of the CD40L gene.
Given the knowledge that abnormal CD40L expression in CD4 T cells is associated with a wide variety of autoimmune and inflammatory diseases, and the mechanism of the abnormal CD40L expression in CD4 T cells is still unknown, we provide a new direction to study and treat these diseases by identifying TFE3 and TFEB as CD40L physiological transcriptional regulators.
Citation
Huan, C. (2006). TFE3 and TFEB are E-cadherin and CD40 ligand transcription activators. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/15932
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Doctoral Dissertation