The ets family of genes encodes transcription factors and binds to purine- rich sequences present in cellular promoters and viral enhancers. The binding of ets1 proteins has been shown to activate cellular promoters/enhancers. The DNA-binding domain of the ets protein is highly conserved among different members of the ets family of genes. The homology is less conserved in the transactivation domain region, suggesting that members of the ets family of genes may be able to modulate target gene activity differently, depending on their specific interaction with other transcription factors. To understand the mechanisms involved in the regulation of ets targeted genes, several approaches have been taken. Nuclear proteins binding to ETS responsive elements (ERE) from hematopoietic and non-hematopoietic cells are being characterized. Many nuclear proteins bind to ERE. One of the ERE protein complexes contains an ets-related protein, GABPalpha, complexed with GABPbeta. This complex is expressed in most of the cell types examined. Specific nuclear protein DNA complexes appear in lymphoid (B- or T-cell origin), myeloid, and erythroid cells. Further characterization of these complexes and their role in regulation of ERE sequences in different cell types is in progress. Ets gene expression is also being studied in peripheral mononuclear cells obtained from different autoimmune patients. To elucidate the molecular mechanisms involved in ets gene function, several independent Jurkat T-cell lines were made which: (i) overexpresses antisense RNA to block mRNA or protein production, (ii) expresses variant forms of ets proteins lacking the DNA-binding domain or the transactiva- tion domain to interfere with normal ets function, and (iii) expresses variant forms of HTLV-I Tax1 and Rex1 proteins to study their effect on ets function. Expression of antisense ets-1 or variant forms of the ets-1 gene products lacking a DNA-binding domain appears to increase lymphokine production, while expression of ets-2 antisense or overexpression of ets-1 inhibits lymphokine production. The role of ets proteins in lymphokine production is under further investigation.
