Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870, USA.
Oncogene. 2010 Apr 8;29(14):2142-52. doi: 10.1038/onc.2009.498. Epub 2010 Jan 25.
Adult T-cell leukemia/lymphoma is a fatal malignancy etiologically linked to infection with the human T-cell leukemia virus (HTLV-1). The virally encoded oncoprotein Tax activates the transcription of HTLV-1 and cellular genes by cooperating with cellular transcription factors. Cyclin D1 is a pivotal regulator of cell cycle progression, and increased expression strongly correlates with malignant transformation. Here, we characterize the mechanism of Tax transactivation of cyclin D1. We find that cyclin D1 transcript levels are elevated in HTLV-1 infected cells and that Tax physically associates with the cyclin D1 gene in vivo. Tax binds the cyclin D1 promoter-proximal cyclic AMP response element (CRE) in the presence of phosphorylated CREB (pCREB) in vitro, and together the Tax-pCREB complex recruits the cellular co-activator p300 to the promoter through this unconventional Tax-responsive element. We further show that the transducer of regulated CREB 2 (TORC2) cooperates with Tax to further enhance p300 recruitment to the cyclin D1 promoter in vitro. Tax and TORC2 in combination stimulate cyclin D1 expression in vivo, demonstrating the functional outcome of the binding interactions. Together, our findings support a model in which Tax-induced accumulation of cyclin D1 shortens the G1 phase of the cell cycle, promotes mitotic replication of the virus, and drives selection and expansion of malignant T-cells.
成人 T 细胞白血病/淋巴瘤是一种致命的恶性肿瘤，其病因与人类 T 细胞白血病病毒（HTLV-1）感染有关。病毒编码的癌蛋白 Tax 通过与细胞转录因子合作，激活 HTLV-1 和细胞基因的转录。细胞周期蛋白 D1 是细胞周期进程的关键调节因子，其表达增加与恶性转化密切相关。在这里，我们描述了 Tax 对细胞周期蛋白 D1 的转录激活机制。我们发现，HTLV-1 感染细胞中环蛋白 D1 的转录水平升高，Tax 体内与细胞周期蛋白 D1 基因发生物理结合。Tax 在体外存在磷酸化 CREB（pCREB）的情况下与细胞周期蛋白 D1 启动子近端 cAMP 反应元件（CRE）结合，并且 Tax-pCREB 复合物通过这种非传统的 Tax 反应元件招募细胞共激活因子 p300 到启动子上。我们进一步表明，调节 CREB 2 的转导物（TORC2）与 Tax 合作，进一步增强 Tax 在体外对细胞周期蛋白 D1 启动子的 p300 募集。Tax 和 TORC2 联合在体内刺激细胞周期蛋白 D1 的表达，证明了结合相互作用的功能结果。总之，我们的研究结果支持这样一种模型，即 Tax 诱导的细胞周期蛋白 D1 积累缩短了细胞的 G1 期，促进了病毒的有丝复制，并推动了恶性 T 细胞的选择和扩增。
