Permatasari Happy Kurnia, Nakahata Shingo, Ichikawa Tomonaga, Morishita Kazuhiro
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):1086-1092. doi: 10.1016/j.bbrc.2017.06.172. Epub 2017 Jun 29.
Human T-cell leukemia virus type 1 (HTLV-1) is a causative agent of adult T-cell leukemia-lymphoma (ATLL). The HTLV-1-encoded protein Tax plays important roles in the proliferation of HTLV-1-infected T-cells by affecting cellular proteins. In this study, we showed that Tax transcriptionally and post-transcriptionally downregulates the expression of the tumor suppressor gene B-cell leukemia/lymphoma 11B (BCL11B), which encodes a lymphoid-related transcription factor. BCL11B expression was downregulated in HTLV-1-infected T-cell lines at the mRNA and protein levels, and forced expression of BCL11B suppressed the proliferation of these cells. The proteasomal inhibitor MG132 increased BCL11B expression in HTLV-1-infected cell lines, and colocalization of Tax with BCL11B was detected in the cytoplasm of HTLV-1-infected T-cells following MG132 treatment. shRNA knock-down of Tax expression also increased the expression of BCL11B in HTLV-1-infected cells. Moreover, we found that Tax physically binds to BCL11B protein and induces the polyubiquitination of BCL11B and proteasome-dependent degradation of BCL11B. Thus, inactivation of BCL11B by Tax protein may play an important role in the Tax-mediated leukemogenesis.
人类嗜T淋巴细胞病毒1型（HTLV-1）是成人T细胞白血病淋巴瘤（ATLL）的病原体。HTLV-1编码的蛋白Tax通过影响细胞蛋白在HTLV-1感染的T细胞增殖中发挥重要作用。在本研究中，我们发现Tax在转录和转录后水平下调肿瘤抑制基因B细胞白血病/淋巴瘤11B（BCL11B）的表达，该基因编码一种与淋巴细胞相关的转录因子。在HTLV-1感染的T细胞系中，BCL11B的mRNA和蛋白水平均下调，而强制表达BCL11B可抑制这些细胞的增殖。蛋白酶体抑制剂MG132可增加HTLV-1感染细胞系中BCL11B的表达，MG132处理后，在HTLV-1感染的T细胞胞质中检测到Tax与BCL11B共定位。敲低Tax表达的shRNA也可增加HTLV-1感染细胞中BCL11B的表达。此外，我们发现Tax与BCL11B蛋白直接结合，并诱导BCL11B的多聚泛素化和蛋白酶体依赖性降解。因此，Tax蛋白使BCL11B失活可能在Tax介导的白血病发生中起重要作用。
