Multiple roles of the epithelium-specific ETS transcription factor, ESE-1, in development and disease

Abstract

The E26 transformation-specific (ETS) family of transcription factors comprises of 27 and 26 members in humans and mice, respectively, which are known to regulate many different biological processes, including cell proliferation, cell differentiation, embryonic development, neoplasia, hematopoiesis, angiogenesis, and inflammation. The epitheliumspecific ETS transcription factor-1 (ESE-1) is a physiologically important ETS transcription factor, which has been shown to play a role in the pathogenesis of various diseases, and was originally characterized as having an epithelial-restricted expression pattern, thus placing it within the epithelium-specific ETS subfamily. Despite a large body of published work on ETS biology, much remains to be learned about the precise functions of ESE-1 and other epithelium-specific ETS factors in regulating diverse disease processes. Clues as to the specific function of ESE-1 in the setting of various diseases can be obtained from studies aimed at examining the expression of putative target genes regulated by ESE-1. Thus, this review will focus primarily on the various roles of ESE-1 in different pathophysiological processes, including regulation of epithelial cell differentiation during both intestinal development and lung regeneration; regulation of dendritic cell-driven T-cell differentiation during allergic airway inflammation; regulation of mammary gland development and breast cancer; and regulation of the effects of inflammatory stimuli within the setting of synovial joint and vascular inflammation. Understanding the exact mechanisms by which ESE-1 regulates these processes can have important implications for the treatment of a wide range of diseases. KEYWORDS: cancer; development; epithelial cell differentiation; ESE-1; ETS transcription factor; inflammation; regeneration The E26 transformation-specific (ETS) family of transcription factors is characterized by a highly conserved 84-aminoacid DNA-binding domain, known as the ETS domain. 1 Because the first member of the ETS family, the v-ets oncogene, was originally discovered as part of a fusion protein with gag and myb expressed by the E26 avian erythroblastosis-transforming retrovirus and its DNA-binding domain is E26 transformation-specific, this 84-amino-acid DNA-binding domain was named the ETS domain. 1 The ETS domain is usually located within the carboxyl-terminal region of the protein as a winged helix-turn-helix structural motif and mediates binding to sites of purine-rich DNA, commonly containing a core consensus sequence of GGAA/T, within the promoter and enhancer regions of target genes. 2,3 Many ETS transcription factors also contain a pointed domain, which is located within the amino-terminal region and is involved in protein-protein interactions. 2 Approximately 30 members of the ETS transcription factor family have been identified in mammals (ie 27 in humans and 26 in mice), 4 and have been shown to play crucial roles in the regulation of many physiological and pathological processes, such as embryonic develo...

Chromatin Profiling Reveals Regulatory Network Shifts and a Protective Role for Hepatocyte Nuclear Factor 4α during Colitis

“…1E, right). This is consistent with AP-1 and ETS roles in mediating the inflammatory response, as both families have been implicated in responding to tumor necrosis factor alpha signaling and have been reported to induce cytokine expression in endothelial and epidermal tissues (28)(29)(30)(31)(32). At genomic regions that lose enhancer chromatin structure upon inflammation, colonic developmental transcription factor motifs predominated (KLF, HNF4, and HNF1), suggesting that these regions lose their transcription factor occupancy during colitis (33)(34)(35)(36)(37).…”

Differential Expression of ETS Family Transcription Factors in NCCIT Human Embryonic Carcinoma Cells upon Retinoic Acid-Induced Differentiation

“…[37][38][39] ESE-1 (also called ELF3, ESX, jen, and ERT) is expressed in various cancer-derived cell lines, as well as in epithelial cellrich tissues, and exerts multiple roles in pathophysiological processes. [40][41][42][43] Null mutation of Elf3, the mouse homolog of human ESE-1, increases the risk of embryonic death in utero, suggesting that ESE-1 plays an important role in embryonic development. 44) Currently, in contrast, little is known about the functional significance of PEA3 and ESE-1 in differentiation, pluripotency, and tumor progression in germ cell-derived cancer cells.…”

Combined Treatment with Epigenetic, Differentiating, and Chemotherapeutic Agents Cooperatively Targets Tumor-Initiating Cells in Triple-Negative Breast Cancer

“…E74-like factor 3 (ELF-3) belongs to the E26 transformation-specific family of transcription factors and is known to regulate epithelial cell differentiation (36). Interestingly, we found that ELF-3 level was lower in the progenitor cell populations from normal breast and tumors, and was restored mainly following E+A and EAD.…”