Activation of cytokine signaling by constitutively active STAT5.

细胞因子有两个主要特征;多个细胞因子的功能冗余和单一细胞因子的复杂功能。我们先前提出了第一个证据，即细胞因子受体的共享亚单位对细胞因子的功能冗余负有责任。在另一方面，细胞因子的复杂功能的分子基础并没有被浓缩。在细胞因子受体中刺激了信号通路，最近识别的JAK-STAT通路现已被广泛研究。有四个JAK激酶和七个STAT转录因子。每个STAT蛋白质激活了许多目标基因，它们可以解释。细胞因子的一种常见的异常功能。However，这是很难识别STAT激活的直接生物结果，因为细胞因子刺激的线索，以同样的信号激活包括JAK-STAT路径的许多信号路径。我们对STAT 5分子，因为STAT 5激活了一种具有令人兴奋功能的细胞因子。 ... More ns. ns.为了研究STAT 5激活的直接生物学结果，我们试图识别使用PCR驱动的随机突变跟踪逆转录病毒介导的表达筛选和识别的稳定活性形式的Stat 5。突变状态5：有固定酪氨酸磷酸化和DNA绑定活动，在Ba/F3细胞中IL-3缺失的诱导表达，以及在B/F3细胞中的Bcl-xL和Pim-1中诱导表达，并在B/F3细胞中与因子无关。出乎意料的，对因子独立Ba/F3细胞的IL-3治疗在24小时内表现出稳定的活性STAT 5结果，或细胞死亡后的差异化。在这些细胞中， mRNA表达的负调节器下游的STAT 5，包括CIS。JAB/SOCS-1/SSI-1和p21 D1 WAF 1/Cip 1 D1是高度诱导的，并且这些负调节器在一个和长时间内持续的表达。在STAT 5-调节基因中，JAB/SOCS-1/SSI-1的稳定表达足以诱导Ba/F3细胞的凋亡，同时在第21页D1 WAF 1/Cip 1D 1诱导这些细胞的宏观差异。Pim-1的稳定表达对IL-3-Ba/F3细胞的独立增长有很大的影响。在添加中，稳定活跃的STAT 5诱导M1隐形细胞的宏观差异，在STAT 5驱动的IL-6生产诱导M1差异通过自主时尚。这些发现建议，即一个单一的转录因子调节细胞的寿命，以确定一组目标基因表达的强度和持续时间。Less（低）

Cytokines have two major characteristics; functional redundancy of multiple cytokines and pleiotropic functions of a single cytokine. We previously presented the first evidence that a shared subunit of cytokine receptors is responsible for the functional redundancy of cytokines. On the other hand, the molecular basis of pleiotropic functions of cytokines has not been elucidated. Among signaling pathways stimulated by cytokine receptors, recently identified JAK-STAT pathway is now extensively studied. There are four JAK kinases and seven STAT transcription factors. Each STAT protein activates many target genes, which may explain. pleiotropic functions of cytokines. However, it has been difficult to identify the direct biological outcome of STAT activation because cytokine stimulation leads to simultaneous activation of many signaling pathways including the JAK-STAT pathway.We were interested in STAT5 molecules because STAT5 is activated by a variety of cytokines with pleiotropic functio … More ns. To study direct biological outcomes of STAT5 activation, we attempted to identify a constitutively active STAT5 using PCR-driven random mutagenesis followed by retrovirus-mediated expression screening, and identified constitutively active forms of STAT5. The mutant STAT5 possessed constitutive tyrosine phosphorylation and DNA binding activity, induced expression of bcl-xL and pim-1 in the absence of IL-3 in Ba/F3 cells, and rendered Ba/F3 cells factor-independent. Unexpectedly, IL-3 treatment of the factor-independent Ba/F3 cells expressing the constitutively active STAT5 resulted in apoptosis within 24 hours, or differentiation followed by cell death. In these cells, mRNA expression of negative regulators downstream of STAT5 including CIS. JAB/SOCS-1/SSI-1, and p21ィイD1WAF1/Cip1ィエD1 were highly induced, and the expression of these negative regulators persisted for a and long period. Of the STAT5-regulated genes, constitutive expression of JAB/SOCS-1/SSI-1 was sufficient to induce apoptosis of Ba/F3 cells, while p21ィイD1WAF1/Cip1ィエD1 induced macrophage differentiation of these cells. Constitutive expression of pim-1 was sufficient to induce IL-3-independent growth of Ba/F3 cells. In addition, the constitutively active STAT5 induced macrophage differentiation of M1 leukemic cells, where STAT5-driven IL-6 production induced M1 differentiation through a autocrine fashion. These findings suggest that a single transcription factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes. Less