Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia
Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia
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DOI：
10.1038/sj.onc.1210984
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发表时间：
2008-05-01
期刊：
影响因子：
8
通讯作者：
Yoshie, O.
中科院分区：
文献类型：
--
作者：
Nakayama, T.;Hieshima, K.;Yoshie, O.
成人T细胞白血病（ATL）是一种成熟的CD 4（+）T细胞恶性肿瘤，病因与人类T细胞白血病病毒1型（HTLV-1）有关。原代ATL细胞经常以高水平表达CCR 4。由于HTLV-1 Tax不诱导CCR 4表达，因此在ATL中组成型活性的转录因子可能是其强表达的原因。我们确定了一个激活蛋白-1（AP-1）的网站在CCR 4启动子作为主要的积极调控元件在ATL细胞。在AP-1家族成员中，Fra-2、JunB和JunD在新鲜的原代ATL细胞中高度表达。一致地，Fra-2/JunB和Fra-2/JunD异源二聚体在Jurkat细胞中强烈激活CCR 4启动子。此外，Fra-2小干扰RNA（siRNA）或JunD siRNA，而不是JunB siRNA，有效地降低ATL细胞中的CCR 4表达和细胞生长。相反，Fra-2或JunD过表达促进Jurkat细胞的细胞生长。我们鉴定了49个基因，包括c-Myb，BCL-6和MDM 2，这些基因在ATL细胞中被Fra-2 siRNA下调。c-Myb、BCL-6和MDM 2也被JunD siRNA下调。与Fra-2一样，这些原癌基因在原代ATL细胞中高度表达，而在正常CD 4（+）T细胞中不表达。总之，Fra-2的异常表达与JunD相关，可能在ATL的CCR 4表达和肿瘤发生中起主要作用。
Adult T-cell leukemia (ATL) is a mature CD4(+) T-cell malignancy etiologically associated with human T-cell leukemia virus type 1 (HTLV-1). Primary ATL cells frequently express CCR4 at high levels. Since HTLV-1 Tax does not induce CCR4 expression, transcription factor(s) constitutively active in ATL may be responsible for its strong expression. We identified an activator protein-1 (AP-1) site in the CCR4 promoter as the major positive regulatory element in ATL cells. Among the AP-1 family members, Fra-2, JunB and JunD are highly expressed in fresh primary ATL cells. Consistently, the Fra-2/JunB and Fra-2/JunD heterodimers strongly activated the CCR4 promoter in Jurkat cells. Furthermore, Fra-2 small interfering RNA (siRNA) or JunD siRNA, but not JunB siRNA, effectively reduced CCR4 expression and cell growth in ATL cells. Conversely, Fra-2 or JunD overexpression promoted cell growth in Jurkat cells. We identified 49 genes, including c-Myb, BCL-6 and MDM2, which were downregulated by Fra-2 siRNA in ATL cells. c-Myb, BCL-6 and MDM2 were also downregulated by JunD siRNA. As Fra-2, these proto-oncogenes were highly expressed in primary ATL cells but not in normal CD4(+) T cells. Collectively, aberrantly expressed Fra-2 in association with JunD may play a major role in CCR4 expression and oncogenesis in ATL.