EFFECT OF HTLV-1 TAX ONCOPROTEIN ON ERΑ ACTIVITIES

Mahmoud Huleihel 1,2 Ammar Abukandil 2
1Department of Microbiology, Immunology and Genetics, Ben Gurion University of the Negev, Beer-Sheva, Israel
2Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel

HTLV-1 Tax oncoprotein is a key factor in HTLV-1 pathogenicity. BRCA1 gene dysfunction can lead to breast cancer development. HTLV-1Tax was found to strongly inhibit BRCA1 expression by preventing the binding of estrogen (E2) receptor alpha (ERα) to BRCA1 promoter. ERα is a potent transcription factor that is involved in the activation of various genes by two different pathways; a classical and non-classical. In classical pathway, ERα binds directly to E2-responsive elements (EREs) located in the appropriate genes promoters and stimulates their transcription. However, in non-classical pathway, the ERα can indirectly bind with promoters and enhance their activity. For instance, ERα activates BRCA1 expression by interacting with jun/fos bound to AP-1 site in BRCA1 promoter.Here we examined Tax effect on ERα induced activation of genes by the classical and non-classical pathway by testing its influence on E2-induced expression of BRCA1 and ERE promoter-driven genes. Our findings showed that E2, as expected, profoundly induced both BRCA1and ERE promoter-driven genes expression. However, while HTLV-1Tax strongly inhibited the estrogen induced activation of BRCA-1 expression, it significantly induced ERE promoter-driven genes expression. So, it seems that HTLV-1 Tax is able to enhance breast epithelial cell replication, through ERα classical pathway and probably other pathways such as NFkB and at the same time to block the E2-ERα induced expression, and possibly functions, of BRCA1. These various HTLV-1 Tax activities in breast epithelial cells may enhance breast cancer development. Our results also proved that only part the reqruited factors are required for the transcriptional activity of ERα complex. Chip assay revealed that the binding of Tax to the ERα complex prevent the ERα complex binding to BRCA-1 promoter while it did not interfere with its link to ERE region. We have also found that Tax inhibits BRCA1-mediated activation of p53-target promoters by inactivating p53.









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