Involvement of Akt pathway in survival of HTLV-I-infected T cells.

磷脂酰肌醇-3激酶（PI-3K）及其下游靶点Akt可被多种刺激激活，并与几种不同的信号通路相关。Akt的一个主要活性是在广泛的细胞中介导细胞存活。在人类t细胞白血病病毒I型（HTLV-I）的白血病发生过程中，Tax已被证明起着关键作用。在本研究中，我们分析了Akt在htlv -i感染的T细胞中的作用。在htlv -i感染的t细胞系中，在表达tax的细胞中检测到Akt的活化。税收通过CREB通路增加Akt活性。我们证明了一种特异性抑制剂LY294002对PI-3K的抑制，在体外诱导表达tax - lv -i的感染t细胞系的细胞凋亡和G_1细胞周期阻滞。相比之下，健康供者的外周血单核细胞和不表达tax的htlv -i感染的t细胞系对PI-3K的抑制具有抗性。LY294002不影响NF-κB和AP-1活性。接下来，我们研究了雷帕霉素选择性抑制Akt下游磷酸化蛋白mTOR阻断细胞周期进程的能力。我们还发现，在htlv -i感染的t细胞系中，雷帕霉素诱导G_1细胞周期阻滞。这些结果表明，htlv -i感染的T细胞存活需要激活除NF-κB和AP-1外的Akt信号通路。

Phosphatidylinositol-3 kinase(PI-3K) and its downstream target Akt are activated by many stimuli and are linked to several different signaling pathways. One major activity of Akt is to mediate cell survival in a broad spectrum of cells. In the leukemogenesis of the human T-cell leukemia virus type I(HTLV-I), Tax has been demonstrated to play a critical role. In the present study we analyzed the role of Akt in HTLV-I-infected T cells. In HTLV-I-infected T-cell lines, the activation of Akt was detected in Tax-expressing cells. Tax increased Akt activity through CREB pathway. We demonstrate that inhibition of PI-3K by a specific inhibitor, LY294002, induced apoptosis and G_1 cell cycle arrest in Tax-expressing HTLV-I-infected T-cell lines in vitro. In contrast, peripheral blood mononuclear cells of healthy donors and Tax-unexpressing HTLV-I-infected T-cell lines were resistant to inhibition of PI-3K. LY294002 did not affect NF-κB and AP-1 activity. Next, we investigated the ability of rapamycin, selectively inhibiting the phosphoprotein mTOR downstream of Akt, to block cell cycle progression. We also showed that rapamycin induced G_1 cell cycle arrest in HTLV-I-infected T-cell lines. These results demonstrate that the activation of Akt signaling pathway, excepting for the NF-κB and AP-1, is required for the cell survival of HTLV-I-infected T cells.