HTLV-1 Tax plays a pivotal role in the viral tra e have shown that the HTLV-1 enhancer, three CRE-containing viral 21bp-repeats in collaboration with the cellular bZip transcription factors, CREB and CREB/ATF-1 heterodimer, form nucleoprotein complexes uniquely capable of interacting with Tax to form ternary complexes that mediate trans- activation. Whereas CREB binds to CRE irrespective of the neighboring DNA sequences, the stable assembly of Tax with CREB and CRE into a ternary complex is dictated by the 5' G-rich and the 3' C-rich flanking sequences in the 21bp-repeats. The molecular basis for the flanking DNA sequence specificity of Tax trans-activation is not clear at present. Tax also directly interacts with cellular transcriptional coactivators, CBP (phospho-CREB binding protein)/p300 whose binding to Tax further assist in the formation of stable quaternary nucleoprotein complexes. Tax in essence, functions as a virus-specific link to connect the transcriptional co-activator, CBP/p300, in a signal-independent manner to un-phosphorylated CREB/ATF-1 assembled on the viral 21bp-repeats. Individual protein domains of Tax and their respective biochemical functions have been delimited. Tax interacts with CREB as a dimer. The NH2 terminal region of Tax binds CREB while the mid-section of Tax is important for dimer formation. The CBP/p300-binding domain of Tax has also been localized to a highly exposed region that lies between the CREB-binding and the Tax subunit-dimerization domains. The aa sequence of this domain bears similarity to that adjacent to the Ser-133 residue of CREB which undergoes signal-introduced phosphorylation to recruit CBP/p300. Most interestingly, when expressed in HeLa cells, this domain and/or its neighboring region induces sever apoptosis. Biochemical analyses of Tax mutants indicate that the recruitment of CBP/p300 alone is not sufficient for trans-activation. Interaction between Tax and other as yet un-identified transcriptional co-activators or basal transcription factors is also required. In this proposal, we seek to elucidate further the mechanisms of HTLV-I Tax action. Major effects will be devoted to: 1:Structure/function analyses of Tax/CREB-bZip/21bp- repeat interaction; 2: Tax interaction with CBP/p300 and other transcription factors; 3: Molecular determinants responsible for Tax- mediate apoptosis; 4: A search for other cellular factors that interact with Tax.
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