PDF(Pubmed)
Abstract：
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma. The oncogene product Tax of HTLV-I is thought to play crucial roles in leukemogenesis by promoting proliferation of the virus-infected cells through activation of growth-promoting genes. These genes code for growth factors and their receptors, cytokines, cell adhesion molecules, growth signal transducers, transcription factors and cell cycle regulators. We show here that Tax activates the gene coding for coactivator-associated arginine methyltransferase 1 (CARM1), which epigenetically enhances gene expression through methylation of histones. Tax activated the Carm1 gene and increased protein expression, not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs). Tax increased R17-methylated histone H3 on the target gene IL-2Rα, concomitant with increased expression of CARM1. Short hairpin RNA (shRNA)-mediated knockdown of CARM1 decreased Tax-mediated induction of IL-2Rα and Cyclin D2 gene expression, reduced E2F activation and inhibited cell cycle progression. Tax acted via response elements in intron 1 of the Carm1 gene, through the NF-κB pathway. These results suggest that Tax-mediated activation of the Carm1 gene contributes to leukemogenic target-gene expression and cell cycle progression, identifying the first epigenetic target gene for Tax-mediated trans-activation in cell growth promotion.
摘要：
人T细胞白血病病毒1型（HTLV-1）是成人T细胞白血病/淋巴瘤的病原体。HTLV-I的癌基因产品税被认为通过激活生长促进基因来促进病毒感染细胞的增殖，从而在白血病发生中起关键作用。这些基因编码生长因子及其受体，细胞因子,细胞粘附分子，生长信号传感器,转录因子和细胞周期调节因子。我们在这里显示Tax激活编码共激活相关精氨酸甲基转移酶1（CARM1）的基因，通过组蛋白甲基化表观遗传学增强基因表达。Tax激活了Carm1基因并增加了蛋白质表达，不仅在人T细胞系中，而且在正常外周血淋巴细胞（PHA-PBLs）中。税收增加了靶基因IL-2Rα上的R17甲基化组蛋白H3，伴随着CARM1的表达增加。短发夹RNA（shRNA）介导的CARM1敲除降低了Tax介导的IL-2Rα和CyclinD2基因表达的诱导，降低E2F活化并抑制细胞周期进程。税收通过Carm1基因内含子1中的反应元件起作用，通过NF-κB途径。这些结果表明，Tax介导的Carm1基因激活有助于白血病靶基因表达和细胞周期进程，确定Tax介导的反式激活促进细胞生长的第一个表观遗传靶基因。
