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首页> 外文期刊>Molecular and Cellular Biology >Anchoring of CREB binding protein to the human T-cell leukemia virus type 1 promoter: a molecular mechanism of Tax transactivation.
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Anchoring of CREB binding protein to the human T-cell leukemia virus type 1 promoter: a molecular mechanism of Tax transactivation.

机译：CREB结合蛋白与人T细胞白血病病毒1型启动子的锚定：Tax反式激活的分子机制。

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摘要

The human T-cell leukemia virus type 1 (HTLV-1)-encoded Tax protein activates viral transcription through interaction with the cellular transcription factor CREB (cyclic AMP response element [CRE] binding protein). Although Tax stabilizes the binding of CREB to the Tax-responsive viral CREs in the HTLV-1 promoter, the precise molecular mechanism by which Tax mediates strong transcriptional activation through CREB remains unclear. In this report, we show that Tax promotes high-affinity binding of the KIX domain of CREB binding protein (CBP) to CREB-viral CRE complexes, increasing the stability of KIX in these nucleoprotein complexes by up to 4.4 kcal/mol. Comparable KIX binding affinities were measured for both phosphorylated and unphosphorylated forms of CREB, and in all cases high-affinity binding was dependent upon both Tax and the viral CRE. Tax also promoted association of KIX to a truncated form of CREB containing only the 73-amino-acid basic leucine zipper (bZIP) domain, indicating that the entire amino-terminal CBP-interacting domain of CREB is nonessential in the presence of Tax. Functional studies upheld the binding studies, as expression of the bZIP domain of CREB was sufficient to support Tax transactivation of HTLV-1 transcription in vivo. Finally, we show that transfection of a KIX expression plasmid, which lacks activation properties, inhibited Tax transactivation in vivo. This suggests that KIX occupies the CBP binding site on Tax, and therefore CBP is likely a cofactor in mediating Tax stimulation of HTLV-1 transcription. Together, these data support a model in which Tax anchors CBP to the HTLV-1 promoter, with strong transcriptional activation resulting from the CBP-associated activities of nucleosome remodeling and recruitment of the general transcription machinery.
机译：人类T细胞白血病病毒1型（HTLV-1）编码的Tax蛋白通过与细胞转录因子CREB（环AMP响应元件[CRE]结合蛋白）相互作用来激活病毒转录。尽管Tax可以稳定CREB与HTLV-1启动子中的Tax响应型病毒CRE的结合，但是Tax能否通过CREB介导强转录激活的确切分子机制仍不清楚。在本报告中，我们表明Tax可促进CREB结合蛋白（CBP）的KIX域与CREB病毒CRE复合物的高亲和力结合，使这些核蛋白复合物中KIX的稳定性提高多达4.4 kcal / mol。对于磷酸化和非磷酸化形式的CREB，都测量了可比的KIX结合亲和力，并且在所有情况下，高亲和力结合都取决于Tax和病毒CRE。 Tax还促进了KIX与仅包含73个氨基酸的碱性亮氨酸拉链（bZIP）结构域的截短形式的CREB的缔合，表明CREB的整个氨基末端CBP相互作用结构域在存在Tax的情况下都是不必要的。功能研究支持结合研究，因为CREB的bZIP结构域的表达足以支持体内HTLV-1转录的Tax转活化。最后，我们显示了缺乏激活特性的KIX表达质粒的转染在体内抑制了Tax反式激活。这表明KIX在Tax上占据了CBP结合位点，因此CBP可能是介导Tax刺激HTLV-1转录的辅助因子。总之，这些数据支持一个模型，其中Tax将CBP锚定到HTLV-1启动子，并具有由CBP相关的核小体重塑和一般转录机制募集的活性而产生的强转录激活作用。

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