INTERACTION OF HTLV-1 TAX WITH CELLULAR REGULATORY PROTEINS

HTLV-1 TAX 与细胞调节蛋白的相互作用

• 批准号: 6100851
• 负责人: J BRADY
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6100851
• 关键词: cell line; cell transformation; chimeric proteins; cytokine; enzyme activity; gel mobility shift assay; gene expression; genetic regulation; glutathione transferase; human T cell lymphotropic virus type 1; lymphocyte; neoplasm /cancer genetics; nuclear factor kappa beta; protein kinase C; protein structure function; tissue /cell culture; transcription factor; tumor suppressor genes; viral carcinogenesis; virus genetics; virus protein

p53 is the most common mutation in human cancers, being inactivated in over half of all human tumors. Inhibition of p53 transcription function, either through mutation or interaction with viral transforming proteins, correlates strongly with oncogenesis. Human T-cell lymphotropic virus type 1 (HTLV-I) is the etiologic agent for adult T-cell leukemia. HTLV-I transforms lymphocytes and the viral encoded protein, Tax, plays a primary role in viral transformation. We have shown that wild- type p53 in HTLV-I transformed cells is stabilized. The present studies were initiated to directly analyze whether the p53 in HTLV-I-transformed cell lines was transcriptionally active and to identify the viral gene product responsible for stabilization and inactivation. Transfection experiments, using a p53-responsive reporter plasmid, and gamma- irradiation studies demonstrate that the wild-type p53 in HTLV-I- transformed cell lines is not fully active. Further, we demonstrate that the HTLV-I transforming protein, Tax, stabilizes and inactivates p53 function. Cotransfection of Tax with p53 results in a greater than 10- fold reduction in p53 transcription activity. Using Gal4/p53 fusion proteins, we demonstrate that Tax inhibition of p53 transactivation function is independent of sequence-specific DNA binding. Moreover, Tax inhibits p53 function by interfering with the activity of the N-terminal activation domain (amino acids 1-52). We conclude that Tax is involved in the inactivation of p53 function and stabilization of p53 in HTLV-I- infected cells. The functional interference of p53 function by Tax may be important for transformation and leukemogenesis.

p53是人类癌症中最常见的突变， 超过一半的人类肿瘤。抑制p53转录功能， 通过突变或与病毒转化蛋白相互作用， 与肿瘤发生密切相关。人嗜t淋巴细胞病毒 1型（HTLV-I）是成人T细胞白血病的病原体。HTLV-I 转化淋巴细胞和病毒编码的蛋白质，税收，发挥作用， 在病毒转化中的主要作用。我们已经证明野生型p53 在HTLV-I转化细胞中稳定。目前的研究是 开始直接分析HTLV-I转化细胞中的p53是否 株系的转录活性，并确定病毒基因 负责稳定和灭活的产品。转染 实验中，使用p53应答报告质粒，和γ- 辐射研究表明，HTLV-1中的野生型p53， 转化的细胞系不是完全活性的。此外，我们证明， HTLV-I转化蛋白Tax稳定并灭活p53 功能Tax与p53的共转染导致大于10- 10%的细胞凋亡。 p53转录活性的倍数降低。使用Gal 4/p53融合 我们证明Tax抑制p53反式激活 功能独立于序列特异性DNA结合。此外，税 通过干扰N-末端的活性来抑制p53功能 激活结构域（氨基酸1-52）。我们得出结论， 在HTLV-I中p53功能的失活和p53的稳定中， 被感染的细胞Tax对p53功能的干预可能 对转化和白血病的发生很重要。