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Clarification of mechanism of HTLV-1 Tax protein on cell immortalization.

阐明HTLV-1 Tax蛋白对细胞永生化的作用机制。

基本信息

批准号：
12470070
负责人：
SHIMOTOHNO Kunitada
金额：
$ 8万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470070/
关键词：
human T-cell leukemia virus p53 trans-activation Tax p73 Tat p53 related genes コレプレッサー TAX コアクチベーターサイクリン p21

项目摘要

Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent for the development of adult T-cell leukemia (ATL). Tax encoded by HTLV-1 plays important role in immortalization of primary human lymphocytes. This study aimed to clarify what roles of Tax was involved in the mechanism of immortalization of cells. We found that Tax interacted with not only co-activator but also co-repressor of transcription. The interaction of Tax with co-activator CBP resulted in suppression of p53 of Tax producing cells. Moreover, we found that p73, a p53 family protein was also trans-suppressed by Tax. Apart from regulation of transcription, Tax is known to regulate cell cycle by interacting or suppressing function of cell cycle inhibitors. P21, one of cycline inhibitors is over-expressed in Tax expressing cells. MT-2 cells which expresses high level of p21 is not arrested at G1. p21 inhibits cell cycle progression by G1 arrest when transiently expressed in COS cells. Co-production of Tax and p21 in COS cells did not sequestered the cell cycle arrest. Thus it is suggested that unidentified mechanism is involved in sequesterthe function of p21 in HTLV-1 infected cells. Clarification of such the mechanism may help to understand Tax dependent immortalization of cells.

人类T细胞白血病病毒1型（HTLV-1）是导致成人T细胞白血病（ATL）发展的病原体。由HTLV-1编码的Tax在人原代淋巴细胞永生化中起重要作用。本研究旨在阐明Tax在细胞永生化机制中的作用。我们发现Tax不仅与转录辅激活子相互作用，而且与转录辅抑制子相互作用。Tax与共激活剂CBP的相互作用导致Tax产生细胞的p53抑制。此外，我们发现p53家族蛋白p73也被Tax反式抑制。除了转录调节外，Tax还通过与细胞周期抑制剂相互作用或抑制其功能来调节细胞周期。细胞周期蛋白抑制剂P21在Tax表达细胞中过表达。高表达p21的MT-2细胞不被阻滞于G1期。当p21在COS细胞中瞬时表达时，其通过G1期阻滞抑制细胞周期进程。在COS细胞中Tax和p21的共同产生并不隔离细胞周期停滞。因此，在HTLV-1感染的细胞中，p21的功能被隔离，这可能是一种未知的机制。阐明这种机制可能有助于理解税收依赖的细胞永生化。