The ets family of genes encodes transcription factors and binds to purine- rich sequences present in cellular promoters and enhancers. The binding of ets1 proteins has been shown to activate cellular promoters (stromelysin, collagenase), enhancers (T-cell receptor alpha) and viral enhancers (human T-cell leukemia virus type I, murine sarcoma virus and polyomavirus). 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. In T-cells, in addition to ETS1, other ETS- related proteins bind to ERE. Further characterization of these proteins is in progress. An ets-related protein, GA binding protein alpha and beta, binds to ERE in the promoter of cytochrome oxidase and ribosomal protein genes. To elucidate the molecular mechanisms involved in ets1 and ets2 function, their activity is blocked in Jurkat T-cells by (i) expressing variant forms of ets proteins lacking either the DNA-binding domain or transactivation domain, (ii) blocking their activity by overexpressing antisense RNA, (iii) expressing variant forms of human T- cell leukemia viral post-transcriptional regulatory protein- Rex, and (iv) overexpressing ets gene products in other hematopoietic and non- hematopoietic cells not expressing ets1 or other ets-related gene products. Characterization of these clones with respect to their growth property, mitogenic requirement, tumorigenicity and effect on ets target genes is under investigation.
