The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal
The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal
复制标题
DOI：
10.1182/blood.v98.6.1935
复制
发表时间：
2001-09-15
期刊：
影响因子：
20.3
通讯作者：
Johnston, JA
中科院分区：
文献类型：
--
作者：
Migone, TS;Humbert, M;Johnston, JA
细胞因子如白细胞介素-2（IL-2）通过其受体的快速酪氨酸磷酸化激活细胞内信号传导途径，导致参与细胞生长和存活的许多基因的激活。去泛素化酶DUB-2响应于IL-2而被诱导，但其功能尚未确定。该研究的结果表明，DUB-2在人T细胞嗜淋巴细胞病毒-I（HTLV-1）转化的T细胞中表达，所述T细胞表现出IL-2 JAK/STAT（信号转导和转录激活因子）途径的组成性激活，并且当在Ba/F3细胞中表达时，DUB-2显著延长IL-2诱导的STAT 5磷酸化。虽然DUB-2没有增强IL-2介导的增殖，但当从生长因子中撤出时，表达DUB-2的细胞具有持续的STAT 5磷酸化和增强的IL-2诱导的基因cis和c-myc的表达。此外，DUB-2表达显著抑制细胞因子撤退诱导的细胞凋亡，使细胞存活。总之，这些数据表明DUB-2可以增强通过JAK/STAT途径的信号传导，延长淋巴细胞存活，并且当组成型表达时，可能有助于在一些转化细胞中观察到的JAK/STAT途径的激活。
Cytokines, such as interleukin-2 (IL-2), activate intracellular signaling pathways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell growth and survival. The deubiquitinating enzyme DUB-2 is induced in response to IL-2 but as yet its function has not been determined. The results of this study show that DUB-2 is expressed in human T-cell lymphotropic virus-I(HTLV-1)-transformed T cells that exhibit constitutive activation of the IL-2 JAK/STAT (signal transducers and activators of transcription) pathway, and when expressed in Ba/F3 cells DUB-2 markedly prolonged IL-2-induced STAT5 phosphorylation. Although DUB-2 did not enhance IL-2-mediated proliferation, when withdrawn from growth factor, cells expressing DUB-2 had sustained STAT5 phosphorylation and enhanced expression of IL-2-induced genes cis and c-myc. Moreover, DUB-2 expression markedly inhibited apoptosis induced by cytokine withdrawal allowing cells to survive. Taken together these data suggest that DUB-2 can enhance signaling through the JAK/STAT pathway, prolong lymphocyte survival, and, when constitutively expressed, may contribute to the activation of the JAK/STAT pathway observed in some transformed cells.