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

Akt 途径参与 HTLV-I 感染的 T 细胞的存活。

基本信息

批准号：
14570988
负责人：
MORI Naoki
金额：
$ 2.05万
依托单位：
University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570988/
关键词：
HTLV-I ATL Akt PI3 kinase mTOR Tax Apoptosis Cell cycle 成人T細胞白血病 NF-κB

项目摘要

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.

磷脂酰肌醇-3激酶（PI-3K）及其下游靶AKT被许多刺激激活，并与几种不同的信号通路相关。 AKT的一种主要活性是介导广泛细胞中的细胞存活。在人类T细胞白血病I型（HTLV-I）的白血病中，税收已被证明起着至关重要的作用。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，在表达税收的细胞中检测到Akt的激活。税收通过CREB途径增加了AKT活动。我们证明，特定抑制剂LY294002对PI-3K的抑制作用，在表达税收的HTLV-I感染的T-T细胞系中诱导的细胞凋亡和G_1细胞周期停滞。相比之下，健康供体的外周血单核细胞和不表现税收的HTLV-I感染的T细胞线对PI-3K的抑制有抵抗力。 LY294002不影响NF-κB和AP-1活性。接下来，我们研究了雷帕霉素的能力，有选择地抑制AKT下游的磷蛋白MTOR MTOR，以阻止细胞周期的进展。我们还表明，雷帕霉素在HTLV-I感染的T细胞系中诱导了G_1细胞周期停滞。这些结果表明，除NF-κB和AP-1外，AKT信号通路的激活是HTLV-I感染的T细胞的生存所必需的。