Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1
Critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1
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DOI：
10.1074/jbc.m308743200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Cross, NCP
中科院分区：
文献类型：
--
作者：
Heath, C;Cross, NCP
8 p11骨髓增生综合征是由靶向染色体带8 p11的获得性易位亚组产生的FGFR 1融合蛋白引起的侵袭性疾病。这些嵌合蛋白具有组成性FGFR 1酪氨酸激酶活性，并被认为以类似于慢性髓性白血病中BCR-ABL的方式解除造血发育的调节。在这里，我们研究了STAT蛋白在这些融合蛋白中最常见的ZNF 198-FGFR 1介导的转化中的作用。我们发现STATs 1、3和5在ZNF 198-FGFR 1转化的Ba/F3细胞中组成性激活，STATs 2、4和6也被酪氨酸磷酸化。显性失活STAT突变体的诱导表明，STAT 5的激活，而不是STATs 1或3，是必不可少的ZNF 198-FGFR 1的抗凋亡作用，STAT 5的激活是必不可少的BclXL在转化细胞中的水平升高。STAT 5的激活也被证明是在细胞因子剥夺条件下BaF 3/ZNF 198-FGFR 1细胞的持续细胞周期进展和DNA修复蛋白Rad 51的上调所必需的。这些发现表明STAT 5激活在ZNF 198-FGFR 1介导的转化中起关键作用。
The 8p11 myeloproliferative syndrome is an aggressive disorder caused by FGFR1 fusion proteins resulting from a subset of acquired translocations that target chromosome band 8p11. These chimeric proteins have constitutive FGFR1 tyrosine kinase activity and are believed to deregulate hemopoietic development in a manner analogous to BCR-ABL in chronic myeloid leukemia. Here we have studied the role of STAT proteins in transformation mediated by the most common of these fusions, ZNF198-FGFR1. We found that STATs 1, 3, and 5 were activated constitutively in ZNF198-FGFR1-transformed Ba/F3 cells and that STATs 2, 4, and 6 were also tyrosine-phosphorylated. Induction of dominant negative STAT mutants showed that activation of STAT5, but not STATs 1 or 3, was essential for the anti-apoptotic effect of ZNF198-FGFR1 and that STAT5 activation is essential for the elevated levels of BclXL in transformed cells. STAT5 activation was also shown to be required for continued cell cycle progression of BaF3/ZNF198-FGFR1 cells in conditions of cytokine deprivation and for up-regulation of the DNA repair protein Rad51. These findings suggest a critical role of STAT5 activation in transformation mediated by ZNF198-FGFR1.