A human T-Cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions
A human T-Cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions
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DOI：
10.1128/mcb.25.14.6178-6198.2005
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Harrod, R
中科院分区：
文献类型：
--
作者：
Awasthi, S;Sharma, A;Harrod, R
人类t细胞嗜淋巴病毒1型（HTLV-1）感染并转化CD4（+）淋巴细胞并引起成人t细胞白血病/淋巴瘤（ATLL），这是一种侵袭性淋巴细胞增生性疾病，通常是致命的。在这里，我们证明HTLV-1 pX剪接变体p30（II）显著增强Myc的转化潜能，并转录激活人类周期蛋白D2启动子，依赖于其保守的Myc响应E-box增强子元件，这与增加的s期进入和多核有关。HTLV-1 p30（II）增强c-Myc转化活性依赖于转录共激活因子、转化转录激活因子蛋白/p434和TIP60，它需要TIP60组蛋白乙酰转移酶（HAT）活性，并与HTLV-1 p30(II)/Myc-TIP60染色质重塑复合物的稳定相关。在培养的htlv -1感染的ATLL患者淋巴细胞中，癌蛋白p30（II）与Myc-TIP60复合物共定位和共免疫沉淀。HTLV-1 p30（II）中的氨基酸残基99至154与TIP60 HAT相互作用，p30（II）通过微阵列基因表达分析确定，以TIP60依赖或TIP60独立的方式转录激活许多细胞基因。重要的是，这些结果表明p30（II）作为myc - tip60转化相互作用的一种新型逆转录病毒调节剂，可能有助于成人t细胞白血病的发生。
The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4(+) lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30(II) markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30(II), is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30(II)/Myc-TIP60 chromatin-remodeling complexes. The p30(II), oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30(II) interact with the TIP60 HAT, and p30(II), transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30(II) functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.