The Ets Gene Family

Transcription factors are critical for proper regulation of cellular proliferation, differentiation and programmed cell death. Alterations in transcription factor function have been shown to cause developmental defects or carcinogenesis. ETS family of transcription factor genes have been isolated and characterized from different organisms, including the human, mouse, rat, chicken, Xenopus, sea urchin, Drosophila and C. ele-gans (reviewed in [3-7]). To date, over 30 members of the ETS family have been identified, including 22 human homologues (see Fig. 1 [8-34]). All ETS genes retain a region of sequence similarity with the v-ETS oncogene of the E26 virus. On the basis of their amino acid sequence identities, we originally defined three regions: A, B and C [8], The A region is localized at the amino terminus and has a moderate degree of amino acid similarity among some ETS family members (e.g., ETS1, ETS2, ERG, ERGB/FLI1 and GABPtt). This region contains weak homology with the helix-loop-helix domain of the HLH family of proteins, also known as the "pointed" domain (PNT, stippled boxes, Fig. 1). In contrast, the middle B region is highly variable between family members and even appears to be dispensable—as in the case of the genes ERG, ERGB/FLI1 and GABPa. We observed that all ETS genes retain a region of conserved sequence, the C domain. This domain contains approximately 85 amino acids that constitute the DNA binding domain (ETS domain, Fig. 1, filled boxes). While located near the carboxyl terminus in many family members, the ETS domain is located at the amino terminus of some family members (e.g., ELK1), as well as near the center of some ets family proteins (e.g., ELF1) (see

Fig. 1). An additional region, designated "R" (Fig. 1, cross-hatched boxes), may be an erg-specific domain based upon sequence conservation between sea urchin, mouse and human erg-related genes. Based on the sequence divergence among ETS family members, they can be divided into 9 subgroups with multiple members. The evolution of these subgroups may have involved duplication of a highly conserved ETS domain, followed by acquisition of divergence by genetic recombination [3, 6],

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