Ets transcription factors in intestinal morphogenesis, homeostasis and disease

Abstract

Ets transcription factors comprise a large family of sequence-specific regulators of gene expression with important and diverse roles in development and disease. Most Ets family members are expressed in the developing and/or mature intestine, frequently in a compartment-specific and temporally dynamic manner. However, with the exception of the highly expressed Elf3, involved in embryonic epithelial differentiation, little is known about Ets functions in intestinal development and homeostasis. Ets factors show altered expression in colon cancer, where they regulate pathways relevant to tumor progression. Ets factors also likely act as important modifiers of non-neoplastic intestinal disease by regulating pathways relevant to tissue injury and repair. Despite a large body of published work on Ets biology, much remains to be learned about the precise functions of this large and diverse gene family in intestinal morphogenesis, homeostasis, and both neoplastic and non-neoplastic pathology.

Fig. 1

Ets expression in the developing mouse intestine. Ets factors with demonstrated developmental expression in the epithelium, nonepithelial tissue (“stroma”), or in whole tissue (unknown sublocalization). Red: genetically inactivated (knocked out) in mouse; asterisk (*): intestinal phenotype reported in knock-out mice.

Fig. 2

Elf3 in developmental enterocyte differentiation. Elf3, expressed in developing intestinal epithelium, promotes epithelial expression of the TGFβ type II receptor (TGFβRII), probably by directly stimulating TGFβRII promoter acivity. This presumably permits an epithelial response to the differentiating effects of TGFβ, thus promoting epithelial differentiation along the enterocyte lineage. The same pathway also appears to regulate goblet cell terminal differentiation (see text).

Fig. 3

Pea3 in colon cancer. Pea3 is overexpressed in tumor cells where it cooperates with the β-catenin/TCF complex and c-Jun to stimulate the expression of the tumor promoter matrilysin. Matrilysin is expressed from early on in the adenoma-carcinoma sequence and may have multiple tumorigenesis-modifying functions (Witty et al., 1994; Takeuchi et al., 1997; Wilson et al., 1997). Other Ets-regulated tumor-promoting targets in colon cancer include Cox-2 and osteopontin, and Ets factors in the stromal, vascular and other surrounding tissue compartments likely also have tumor-modifying functions (see text).