Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells
Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells
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DOI：
10.1016/s0145-2126(03)00158-9
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发表时间：
2004-01-01
影响因子：
2.7
通讯作者：
Marasco, WA
中科院分区：
文献类型：
--
作者：
Cheng, JH;Zhang, DS;Marasco, WA
成人T细胞白血病（ATL）是一种侵袭性恶性肿瘤，与人类T细胞嗜淋巴细胞病毒1（HTLV-1）感染有关。HTLV-1转化的T细胞系和新鲜ATL细胞的特征在于白细胞介素-2受体（IL-2 R）信号传导途径的组成性活化，然而，负责组成性IL-2 R活化的机制是未知的。为了进一步研究该信号传导途径失调的原因，我们分别通过实时PCR和蛋白质印迹法测量IL-2 R信号传导途径的四种负调节物的mRNA和蛋白质表达水平，所述负调节物包括含src同源性2（SH 2）的磷酸酶（SHP）、含丝氨酸诱导（CIS）SH 2的蛋白质、细胞因子信号转导抑制因子-1（SOCS 1）和活化信号转导和转录激活因子3（STAT 3）蛋白抑制因子（PIAS 3）在6个HTLV-1阴性和7个HTLV-1阳性T细胞白血病细胞系中的表达。还检查了JAK/STAT途径的激活状态。在所有HTLV-1感染的转化细胞系中，SHP 1 mRNA和蛋白表达水平选择性下调，而CIS、SOCS 1和PIAS 3蛋白表达显著但不显著上调，并且细胞显示出组成性STAT 3活化的证据。在急性HTLV-1感染的原代CD 4（+）T细胞中，培养10周后SHP 1表达逐渐丧失，这与从永生化到转化的进展以及生长对IL-2依赖性的丧失相关。HTLV-1感染后建立的两个转化细胞系显示SHP 1表达缺失和CIS、SOCS 1、PIAS 3过表达。然而，这种过表达不足以阻断JAK/STAT途径的组成性激活。因此，在HTLV-1转化的细胞中发现多个水平的IL-2受体信号失调，这可能是SHP 1表达早期丧失的结果。(C)2003爱思唯尔有限公司。保留所有权利。
Adult T-cell leukemia (ATL) is an aggressive malignancy that is associated with human T-cell lymphotropic virus 1 (HTLV-1) infection. HTLV-1 transformed T-cell lines and fresh ATL cells are characterized by constitutive activation of the interleukin-2 receptor (IL-2R) signaling pathway however, the mechanism(s) responsible for constitutive IL-2R activation are unknown. To further examine the cause of this signaling pathway deregulation, we measured mRNA and protein expression levels by real-time PCR and Western blots, respectively, of four negative regulators of the IL-2R signaling pathway including src homology 2 (SH2)-containing phosphatase (SHP]), cytokine-inducible (CIS) SH2-containing protein, suppressor of cytokine signaling-1 (SOCS1) and protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) in six HTLV-1 negative and seven HTLV-1 positive T-cell leukemia lines. The activation status of the JAK/STAT pathway was also examined. SHP1 mRNA and protein expression levels were selectively down regulated in all HTLV-1-infected transformed cell lines, while CIS, SOCS 1, and PIAS3 protein expression were markedly but variably upregulated and the cells showed evidence of constitutive STAT3 activation. In acutely HTLV-1 infected primary CD4(+) T-cells there was a gradual loss of SHP1 expression over 10 weeks in culture which correlated with progression from immortalization to transformation and loss of IL-2 dependence for growth. Two transformed cell lines that were established following HTLV-1 infection showed loss of SHP1 expression and overexpression of CIS, SOCS1, PIAS3. However, this overexpression was not adequate to block constitutive activation of the JAK/STAT pathway. Thus, multiple levels of IL-2 receptor signal deregulation are found in HTLV-1 transformed cells, which may be a result of early loss of SHP1 expression. (C) 2003 Elsevier Ltd. All rights reserved.