The Epithelium-specific ETS Protein EHF/ESE-3 Is a Context-dependent Transcriptional Repressor Downstream of MAPK Signaling Cascades

Abstract

Exon trapping and cDNA selection procedures were used to search for novel genes at human chromosome 11p13, a region previously associated with loss of heterozygosity in epithelial carcinomas. Using these approaches, we found the ESE-2 and ESE-3 genes, coding for ETS domain-containing transcription factors. These genes lie in close proximity to the catalase gene within a ϳ200-kilobase genomic interval. ESE-3 mRNA is widely expressed in human tissues with high epithelial content, and immunohistochemical analysis with a newly generated monoclonal antibody revealed that ESE-3 is a nuclear protein expressed exclusively in differentiated epithelial cells and that it is absent in the epithelial carcinomas tested. In transient transfections, ESE-3 behaves as a repressor of the Ras-or phorbol ester-induced transcriptional activation of a subset of promoters that contain ETS and AP-1 binding sites. ESE-3-mediated repression is sequence-and context-dependent and depends both on the presence of high affinity ESE-3 binding sites in combination with AP-1 cis-elements and the arrangement of these sites within a given promoter. We propose that ESE-3 might be an important determinant in the control of epithelial differentiation, as a modulator of the nuclear response to mitogen-activated protein kinase signaling cascades. Intracellular signaling through mitogen-activated protein (MAP)1 kinases is a universal mechanism controlling multiple aspects of cell division, migration, and differentiation (1). Among the known nuclear effectors downstream of MAP kinase signaling cascades are members of the ETS family of transcription factors, a group of proteins that share a conserved DNA binding domain, known as the ETS domain, and that are only found in metazoans. ETS transcription factors have been implicated as positive and negative regulators in signal transduction pathways that control a number of cellular processes, including differentiation, proliferation, cellular migration or invasion, and inflammation, and some of these factors are indeed direct targets of MAP kinases (2-5).The biological role of ETS proteins in the integration of signals from MAP kinases has been best characterized in Drosophila melanogaster. Genetic and biochemical studies have led to the identification of two ETS proteins, Pointed and Anterior Open (Aop)/Yan, as pivotal components in the nuclear integration of MAPK signaling cascades (6 -10). The activity of Pointed P2, a product of the pointed gene (11), and a putative ortholog of the vertebrate ETS-1 and ETS-2 proteins (12, 3), is dependent upon direct phosphorylation by MAP kinases. On the other hand, Aop/Yan has been described as a repressor of Pointed-responsive genes (6 -10) and is also a downstream target of MAP kinase cascades. No mammalian epithelial ortholog of Aop/Yan has been identified yet. It has been proposed that phosphorylation of Aop/Yan by MAP kinases results in its inactivation and nuclear export, thus alleviating repression and allowing the transcriptional activation of Pointed target gene...

Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

“…32 Functionally, this protein has been shown to be a transcriptional repressor of several genes positively regulated by MAP kinase signaling. 33 As ascertained by western blotting, ESE-3 protein was completely eliminated in nuclear extracts obtained from APCs stimulated with various TLR ligands and incubated with IL-10 ( Figure 4).…”

Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

“…Together with our finding that ESE-3 is upregulated by cytokines in bronchial epithelial cells, this supports the idea that ESE-3 may play a role in the pathogenesis of asthma. It has been shown that ESE-3 represses expression of the matrix metalloproteinase MMP-1 [18,26]. MMPs mediate extracellular matrix remodeling during processes such as wound repair [40,41].…”

“…Many Ets family members are expressed in hematopoietic cells [13]. However, the three ESE transcription factors are expressed only in organs that have specialized epithelial cells, such as intestine, kidney, prostate, pancreas and lung [8,9,[14][15][16][17][18][19][20]. ESE-1 is expressed in many different organs, whereas ESE-2 and ESE-3 expression is more restricted to the glandular organs, such as the salivary gland, mammary gland and prostate.…”

“…ESE-1, ESE-2 and ESE-3 are expressed at high levels in the trachea. In the lung ESE-2 is expressed only at low levels, whereas both ESE-1 and ESE-3 are moderately expressed [8,9,[14][15][16][17][18][19][20].…”

Epithelium-specific ets transcription factor 2 upregulates cytokeratin 18 expression in pulmonary epithelial cells through an interaction with cytokeratin 18 intron 1

“…Since then, more than 30 Ets family members have been identified [2,3]. These proteins are expressed mainly in hematopoietic cells [4,5], however some are also expressed in epithelial cells [6][7][8][9][10][11]. Ets factors are known to play roles in skeletal development, haematopoiesis, neural synapse formation, immunomodulation, metastasis, cellular proliferation and differentiation, and apoptosis [12][13][14].…”