HTLV-I Tax dysregulates β-catenin signaling

β-连环蛋白信号的失调与细胞的恶性转化有关。然而，β-连环蛋白在人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。在这里，我们发现β-catenin蛋白在细胞核中过表达，并且β-catenin依赖的转录在tax -阳性htlv -1感染的t细胞系中显著增强，与tax -阴性htlv -1感染的t细胞系相比。瞬时转染Tax似乎通过激活cAMP反应元件结合蛋白来稳定β-catenin蛋白，从而增强β-catenin依赖性转录。htlv -1感染的过表达β-catenin的t细胞系也表现出Akt活性的增加，这是通过cAMP反应元件结合蛋白的Tax激活，导致糖原合成酶激酶3β的磷酸化和失活，而糖原合成酶激酶3β磷酸化β-catenin进行泛素化。磷脂酰肌醇3-激酶抑制剂LY294002降低了税阳性t细胞系中β-catenin的表达，氯化锂灭活糖原合成酶激酶3β后，恢复了氧阴性t细胞系中β-catenin的表达。最后，我们发现显性负Akt抑制了税收诱导的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感染的T细胞转化中很重要。

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.