Neurokinin-B transcription in erythroid cells - Direct activation by the hematopoietic transcription factor GATA-1
Neurokinin-B transcription in erythroid cells - Direct activation by the hematopoietic transcription factor GATA-1
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DOI：
10.1074/jbc.m403475200
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发表时间：
2004-07-23
影响因子：
4.8
通讯作者：
Bresnick, EH
中科院分区：
文献类型：
--
作者：
Pal, S;Nemeth, MJ;Bresnick, EH
转录因子的加塔家族建立控制发育过程的遗传网络，包括造血、血管发生和心脏发生。我们发现，加塔-1强烈激活Tac-2基因的转录，Tac-2基因编码前神经激肽-B，神经激肽-B（NK-B）的前体。神经激肽通过G蛋白偶联的跨膜受体介导多种生理反应，包括疼痛感知和血管张力的控制。而NK-B水平升高与妊娠相关的先兆子痫有关（Page，N. M.，伍兹河J.，加德纳，S。M.，Lomthaisong，K.，格拉德韦尔河T.，Butlin，D. J.，马尼翁达岛T.，和Lowry，P. J.（2000）Nature 405，797 - 800），对NK-B合成和功能的调节了解甚少。Tac-2在正常小鼠红系细胞中表达，并在离体红细胞生成后被诱导。雌激素受体与加塔-1的融合体（ER-加塔-1）和内源性加塔-1均占据Tac-2内含子-7的一个区域，该区域包含两个保守的加塔基序。G1细胞中加塔-1基因缺失的遗传互补分析显示，内源性加塔-2占据内含子7的同一区域，ER-加塔-1的表达取代了加塔-2，激活了Tac-2的转录。红系细胞不表达神经激肽受体，而主动脉和卵黄囊内皮细胞差异表达神经激肽受体亚型。由于NK-B在卵黄囊内皮细胞中诱导cAMP积累，这些结果提示了一种新的血管调节模式，其中加塔-1控制红系细胞中的NK-B合成。
The GATA family of transcription factors establishes genetic networks that control developmental processes including hematopoiesis, vasculogenesis, and cardiogenesis. We found that GATA-1 strongly activates transcription of the Tac-2 gene, which encodes proneurokinin-B, a precursor of neurokinin-B (NK-B). Neurokinins function through G protein-coupled transmembrane receptors to mediate diverse physiological responses including pain perception and the control of vascular tone. Whereas an elevated level of NK-B was implicated in pregnancy-associated pre-eclampsia ( Page, N. M., Woods, R. J., Gardiner, S. M., Lomthaisong, K., Gladwell, R. T., Butlin, D. J., Manyonda, I. T., and Lowry, P. J. ( 2000) Nature 405, 797 - 800), the regulation of NK-B synthesis and function are poorly understood. Tac-2 was expressed in normal murine erythroid cells and was induced upon ex vivo erythropoiesis. An estrogen receptor fusion to GATA-1 (ER-GATA-1) and endogenous GATA-1 both occupied a region of Tac-2 intron-7, which contains two conserved GATA motifs. Genetic complementation analysis in GATA-1-null G1E cells revealed that endogenous GATA-2 occupied the same region of intron-7, and expression of ER-GATA-1 displaced GATA-2 and activated Tac-2 transcription. Erythroid cells did not express neurokinin receptors, whereas aortic and yolk sac endothelial cells differentially expressed neurokinin receptor subtypes. Since NK-B induced cAMP accumulation in yolk sac endothelial cells, these results suggest a new mode of vascular regulation in which GATA-1 controls NK-B synthesis in erythroid cells.