Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells
Transcriptional regulation of the cyclin D1 promoter by STAT5: its involvement in cytokine-dependent growth of hematopoietic cells
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DOI：
10.1093/emboj/18.5.1367
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发表时间：
1999-03-01
期刊：
影响因子：
11.4
通讯作者：
Kanakura, Y
中科院分区：
文献类型：
--
作者：
Matsumura, I;Kitamura, T;Kanakura, Y
STAT 5是参与许多激素和细胞因子的信号转导途径的转录因子家族的成员，尽管STAT 5被认为在细胞因子的生物学效应中起关键作用，但其与细胞生长控制相关的下游靶标在很大程度上是未知的。在人白细胞介素-3（IL-3）依赖性细胞系F-36 P-mpl中，显性负性（dn）-STAT 5和dn-ras的诱导表达导致IL-3依赖性细胞生长的抑制，伴随细胞周期蛋白D1 mRNA表达的减少。此外，STAT 5A（1*6-STAT 5A）和ras（H-ras（G12 V））的组成型活性形式都能够使F-36 P-mpl细胞在不添加生长因子的情况下增殖。在NIH 3 T3细胞中，1*6-STAT 5A和N-ras（G12 V）在荧光素酶测定中单独和协同反式激活细胞周期蛋白D1启动子。在F-36 P-mpl细胞中，dn-STAT 5和dn-ras均能抑制IL-3诱导的cyclin D1启动子活性。使用一系列突变的cyclin D1启动子，发现1*6-STAT 5A通过-481 bp的潜在STAT结合序列反式激活cyclin D1启动子。dn-STAT 5对IL-3依赖性生长的抑制作用通过细胞周期蛋白D1的表达而恢复。因此，除了ras信号传导外，STAT 5似乎还介导细胞周期蛋白D1的转录调节，从而有助于造血细胞的细胞周期蛋白依赖性生长。
STAT5 is a member of a family of transcription factors that participate in the signal transduction pathways of many hormones and cytokines, Although STAT5 is suggested to play a crucial role in the biological effects of cytokines, its downstream target(s) associated with cell growth control is largely unknown. In a human interleukin-3 (IL-3)-dependent cell line F-36P-mpl, the induced expression of dominant-negative (dn)-STAT5 and of dn-ras led to inhibition of IL-3-dependent cell growth, accompanying the reduced expression of cyclin D1 mRNA. Also, both constitutively active forms of STAT5A (1*6-STAT5A) and ras (H-ras(G12V)) enabled F-36P-mpl cells to proliferate without added growth factors. In NIH 3T3 cells, 1*6-STAT5A and N-ras(G12V) individually and cooperatively transactivated the cyclin D1 promoter in luciferase assays. Both dn-STAT5 and dn-ras suppressed IL-3-induced cyclin D1 promoter activities in F-36P-mpl cells, Using a series of mutant cyclin DI promoters, 1*6-STAT5A was found to transactivate the cyclin D1 promoter through the potential STAT-binding sequence at -481 bp, In electrophoretic mobility shift assays, STAT5 bound to the element in response to IL-3, Furthermore, the inhibitory effect of dn-STAT5 on IL-3-dependent growth was restored by expression of cyclin DI, Thus STAT5, in addition to ras signaling, appears to mediate transcriptional regulation of cyclin D1, thereby contributing to cytokine-dependent growth of hematopoietic cells.