PROPERTIES TO THE HTLV I TAX PROTEIN

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DESCRIPTION (adapted from applicant's abstract): HTLV-I Tax protein is critical for the activation of gene expression through both the CREB and NF-kB transcriptional pathways and is also responsible for the transformation of T-lymphocytes. Tax activates HTLV-I gene expression through three regulatory elements in the LTR known as the 21 bp repeats that contain binding sites for the ATF/CREB family. However, Tax will not activate gene expression from cellular promoters containing CRE elements, indicating that the overall structure of the 21 bp repeats is critical for its activation. Tax also activates gene expression via NF-kB binding sites and increases the gene expression of specific cellular genes. Dr. Gaynor's studies indicate that direct interactions between CREB and Tax result in the formation of a stable complex on the 21 bp repeats which markedly increases the recruitment of the coactivator CBP. CBP binds to a number of different cellular regulatory proteins including CREB and it is likely involved in bridging factors bound to upstream control elements with components of the basal transcription complex. Recent studies also indicate that CBP can directly interact with NF-kB proteins. Tax activation via NF-kB binding sites is potentially mediated through both direct or indirect interactions of Tax with NF-kB proteins and by Tax activation of cellular kinases that phosphorylate IkB resulting in its degradation and the constitutive nuclear expression of NF-kB. Four specific aims are proposed to extend these studies and to characterize cellular factors that modulate Tax function in an effort to determine its mechanism of action. The aims are: (1) to identify cellular factors that associate with Tax, (2) to determine the function of those factors, (3) to analyze how CBP modulates Tax activation via CREB and NF-kB pathways, and (4) to determine how Tax modulates the activity of kinases that phosphorylate IkB. The overall objective is to increase understanding of the mechanism of Tax transcriptional activation and transformation.