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GA结合蛋白与c-Myb和C/EBP协同激活中性粒细胞弹性蛋白酶启动子。

GABP cooperates with c-Myb and C/EBP to activate the neutrophil elastase promoter.

作者信息

Nuchprayoon I, Simkevich C P, Luo M, Friedman A D, Rosmarin A G

机构信息

Division of Pediatric Oncology, The Johns Hopkins Oncology Center, Johns Hopkins University, Baltimore, MD, USA.

出版信息

Blood. 1997 Jun 15;89(12):4546-54.

PMID:9192779
Abstract

Neutrophil elastase (NE) is a serine protease that is transcriptionally regulated during early myeloid differentiation. The murine NE (mNE) promoter contains functionally important c-Myb, C/EBP, and ets binding sites. Deletion of the ets site reduced promoter activity by 90%. Although the ets transcription factor, PU.1, bound to this ets site, it only modestly activated the mNE promoter. Here, we show that a second transcription factor from myeloid cells-GABP-binds to the mNE ets site but strongly activates the mNE promoter. GABP is a heteromeric transcription factor complex that consists of GABP alpha, an ets factor, and GABP beta, a Notch-related protein. GABP alpha bound to the mNE ets site and, in turn, recruited GABP beta to form a transcriptionally active complex. GABP alpha and PU.1 competed with each other for binding to the mNE ets site. GABP increased the activity of the mNE promoter sevenfold in U937 myeloid cells. GABP cooperated with c-Myb and C/EBP alpha to activate the mNE promoter more than 85-fold in otherwise nonpermissive, nonhematopoietic NIH 3T3 cells. Thus, GABP binds to the crucial mNE promoter ets site and powerfully activates its expression alone and in cooperation with the transcription factors c-Myb and C/EBP.

摘要

中性粒细胞弹性蛋白酶(NE)是一种丝氨酸蛋白酶,在早期髓系分化过程中受到转录调控。小鼠NE(mNE)启动子包含功能重要的c-Myb、C/EBP和ets结合位点。ets位点的缺失使启动子活性降低了90%。尽管ets转录因子PU.1与该ets位点结合,但它对mNE启动子的激活作用较小。在此,我们表明来自髓系细胞的另一种转录因子——GA结合蛋白(GABP)——与mNE的ets位点结合,但能强烈激活mNE启动子。GABP是一种异源转录因子复合物,由ets因子GABPα和Notch相关蛋白GABPβ组成。GABPα与mNE的ets位点结合,进而招募GABPβ形成转录活性复合物。GABPα和PU.1相互竞争结合mNE的ets位点。在U937髓系细胞中,GABP使mNE启动子的活性提高了7倍。在原本不允许、非造血的NIH 3T3细胞中,GABP与c-Myb和C/EBPα协同作用,使mNE启动子的活性激活超过85倍。因此,GABP与关键的mNE启动子ets位点结合,并单独或与转录因子c-Myb和C/EBP协同作用,有力地激活其表达。

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