The epithelium-specific ETS protein EHF/ESE-3 is a context-dependent transcriptional repressor downstream of MAPK signaling cascades.

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 approximately 200-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.

brother of rhomboid, a rhomboid-related gene expressed during early Drosophila oogenesis, promotes EGF-R/MAPK signaling.

The Drosophila rhomboid (rho) gene participates in localized activation of EGF-receptor signaling in various developmental settings. The Rhomboid protein has been proposed to promote presentation and/or processing of the membrane-bound Spitz (mSpi) EGF-related ligand to generate an active diffusible form of the ligand. Here, we report on a new rhomboid-related gene identified by sequence similarity searching that we have named brother of rhomboid (brho). In contrast to rho, which is expressed in complex patterns during many stages of development, brho appears to be expressed only during oogenesis. brho transcripts are present in early oocytes and abut posterior follicle cells which exhibit high levels of MAPK activation. brho, like rho, collaborates with Star to promote signaling through the EGF-R/MAPK pathway, and genetic evidence indicates that Brho can activate both the mSpi and the Grk precursor EGF ligands in the wing. We propose that endogenous brho may activate the oocyte-specific Gurken ligand and thereby participate in defining posterior cell fates in the early follicular epithelium.

Homeobrain, a novel paired-like homeobox gene is expressed in the Drosophila brain.

The homeobrain (hbn) gene is a new paired-like homeobox gene which is expressed in the embryonic brain and the ventral nerve cord. Expression of homeobrain initiates during the blastoderm stage in the anterior dorsal head primordia and the gene is persistently expressed in these cells which form parts of the brain during later embryonic stages. An additional weaker expression pattern is detected in cells of the ventral nerve cord from stage 11 on. The homeodomain in the Homeobrain protein is most similar to the Drosophila proteins DRx, Aristaless and Munster. In addition, the localized brain expression patterns of homeobrain and DRx resemble each other. Two other homeobox genes, orthopedia and DRx are clustered in the 57B region along with homeobrain. The current evidence indicates that homeobrain, DRx and orthopedia form a homeobox gene cluster in which all the members are expressed in specific embryonic brain subregions.

spen encodes an RNP motif protein that interacts with Hox pathways to repress the development of head-like sclerites in the Drosophila trunk.

Drosophila has eight Hox proteins, and they require factors acting in parallel to regulate different segmental morphologies. Here we find that the Drosophila gene split ends (spen), has a homeotic mutant phenotype, and appears to encode such a parallel factor. Our results indicate that spen plays two important segment identity roles. One is to promote sclerite development in the head region, in parallel with Hox genes; the other is to cooperate with Antennapedia and teashirt to suppress head-like sclerite development in the thorax. Our results also indicate that without spen and teashirt functions, Antennapedia loses its ability to specify thoracic identity in the epidermis. spen transcripts encode extraordinarily large protein isoforms (approx. 5,500 amino acids), which are concentrated in embryonic nuclei. Both Spen protein isoforms and Spen-like proteins in other animals possess a clustered repeat of three RNP (or RRM) domains, as well as a conserved motif of 165 amino acids (SPOC domain) at their C-termini. Spen is the only known homeotic protein with RNP binding motifs, which indicates that splicing, transport, or other RNA regulatory steps are involved in the diversification of segmental morphology. Previous studies by Dickson and others (Dickson, B. J., Van Der Straten, A., Dominguez, M. and Hafen, E. (1996). Genetics 142, 163-171) identified spen as a gene that acts downstream of Raf to suppress Raf signaling in a manner similar to the ETS transcription factor Aop/Yan. This raises the intriguing possibility that the Spen RNP protein might integrate signals from both the Raf and Hox pathways.