HTLV-I Tax dysregulates β-catenin signaling

β-连环蛋白信号转导的失调与细胞的恶性转化有关。然而，β-连环蛋白在人类T细胞白血病病毒1型（HTLV-1）诱导的T细胞转化中的作用尚不清楚。我们发现β-catenin蛋白在细胞核中过表达，并且与Tax阴性HTLV-1感染的T细胞系相比，Tax阳性HTLV-1感染的T细胞系中β-catenin依赖性转录显著增强。Tax的瞬时转染似乎通过稳定β-catenin蛋白，经由cAMP反应元件结合蛋白的活化来增强β-catenin依赖性转录。过表达β-连环蛋白的HTLV-1感染的T细胞系也显示Akt活性增加，通过Tax激活cAMP反应元件结合蛋白，导致糖原合成酶激酶-3 β磷酸化和失活，糖原合成酶激酶-3 β磷酸化β-连环蛋白用于泛素化。磷脂酰肌醇3-激酶抑制剂LY 294002可降低Tax阳性T细胞系中β-连环蛋白的表达，氯化锂灭活糖原合成酶激酶-3 β可恢复Tax阴性T细胞系中β-连环蛋白的表达。最后，我们发现显性失活Akt抑制Tax诱导的β-catenin依赖性转录。这些结果表明Tax通过Akt信号通路激活β-catenin。我们的研究结果表明，Tax激活β-catenin可能在HTLV-1感染转化T细胞中起重要作用。

Dysregulation of β-catenin signaling has been implicated in the malignant transformation of cells. However, the role of β-catenin in human T-cell leukemia virus type 1 (HTLV-1)-induced transformation of T cells is unknown. Here we found that β-catenin protein was overexpressed in the nucleus and that β-catenin-dependent transcription was significantly enhanced in Tax-positive HTLV-1-infected T-cell lines, compared to Tax-negative HTLV-1-infected T-cell-lines. Transient transfection of Tax appeared to enhance the β-catenin-dependent transcription by stabilizing the β-catenin protein, via activation of the cAMP response element-binding protein. The HTLV-1-infected T-cell lines overexpressing β-catenin also showed increased Akt activity, via Tax activation of cAMP response element-binding protein, resulting in the phosphorylation and inactivation of glycogen synthase kinase-3β, which phosphorylates β-catenin for ubiquitination. The phosphatidylinositol 3-kinase inhibitor, LY294002 reduced β-catenin expression in Tax-positive T-cell lines, and inactivation of glycogen synthase kinase-3β by lithium chloride restored β-catenin expression in Tox-negative T-cell lines. Finally, we showed that dominant-negative Akt inhibited the Tax-induced β-catenin-dependent transcription. These results indicated that Tax activates β-catenin through the Akt signaling pathway. Our findings suggest that activation of β-catenin by Tax may be important in the transformation of T cells by HTLV-1 infection.