Activation of STAT signaling pathways and induction of suppressors of cytokine signaling (SOCS) proteins in mammalian lens by growth factors
Activation of STAT signaling pathways and induction of suppressors of cytokine signaling (SOCS) proteins in mammalian lens by growth factors
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DOI：
10.1167/iovs.03-0311
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发表时间：
2004-03-01
影响因子：
4.4
通讯作者：
Egwuagu, CE
中科院分区：
文献类型：
--
作者：
Ebong, S;Yu, CR;Egwuagu, CE
目的.本研究旨在检测生长因子在透镜中的作用是否通过Janus激酶/信号转导和转录激活因子（JAK/STAT）途径介导，以及它们是否诱导细胞因子信号转导抑制因子（SOCS）的表达，SOCS是一个新的细胞因子和生长因子活性反馈调节因子家族。通过免疫组化、RTPCR、北方、Western、增殖或瞬时报告基因分析，分析了转基因或野生型小鼠透镜和用生长因子刺激的透镜上皮细胞中STAT激活和SOCS表达。STAT在透镜中以低水平组成性表达，并被胰岛素样生长因子（IGF）-1、血小板衍生生长因子（PDGF）-aa和FGF-1或-2激活。STAT信号传导的强度在高FGF-2浓度下增加，并且FGF与IGF-1或PDGFaa协同作用以增强STAT信号传导和SOCS表达。AG-490可抑制生长因子诱导的透镜细胞增殖，AG-490是JAK 2/STAT 3的特异性抑制剂。这是第一份报告，FGF激活STAT途径在透镜和SOCS蛋白组成型表达和上调生长因子在这个组织。通过JAK/STAT途径抑制剂对透镜细胞增殖的抑制以及透镜中具有组成性激活的STAT 1的转基因小鼠后极中透镜上皮细胞的异常增殖，强调了透镜中STAT途径的生理相关性。FGF-1、FGF-2、IGF-1或PDGFaa对STAT通路的共同激活及其对透镜细胞中STAT和SOCS的协同激活表明，这些因子之间的活性和串扰对透镜中激活的STAT的稳态水平敏感，并且可能处于SOCS家族蛋白的反馈调节下。
PURPOSE. This study was conducted to examine whether the effects of growth factors are mediated in the lens by Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways and whether they induce expression of suppressors of cytokine signaling (SOCS), a novel family of feedback regulators of cytokine and growth factor activities.METHODS. STAT activation and SOCS expression were analyzed in transgenic or wild-type mouse lens and lens epithelial cells stimulated with growth factors by immunohistochemistry, RTPCR, Northern, Western, proliferation, or transient reporter assays.RESULTS. STATs were constitutively expressed at low levels and activated by insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF)-aa, and FGF-1 or -2 in the lens. The Intensity of STAT signaling increased at high FGF-2 concentration and FGFs act in synergy with IGF-1 or PDGFaa to enhance STAT signaling and SOCS expression. Growth factor-induced proliferation of lens cells is inhibited by AG-490, a specific inhibitor of JAK2/STAT3.CONCLUSIONS. This is the first report that FGFs activate STAT pathways in the lens and that SOCS proteins are constitutively expressed and upregulated by growth factors in this tissue. Physiological relevance of STAT pathways in the lens is underscored by inhibition of lens cell proliferation by inhibitors of JAK/STAT pathways and by the aberrant proliferation of lens epithelium in the posterior pole of transgenic mice with constitutively activated STAT1 in the lens. Common activation of STAT pathways by FGF-1, FGF-2, IGF-1, or PDGFaa and their synergistic activation of STATs and SOCS in lens cells suggest that activities and crosstalk between these factors are sensitive to the steady state levels of activated STATs in the lens and may be under feedback regulation by SOCS family proteins.