Inhibitory Effect of AP-1 Complex on 5-Aminolevulinate Synthase Gene Expression through Sequestration of cAMP-response Element Protein (CRE)-binding Protein (CBP) Coactivator*
Inhibitory Effect of AP-1 Complex on 5-Aminolevulinate Synthase Gene Expression through Sequestration of cAMP-response Element Protein (CRE)-binding Protein (CBP) Coactivator*
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AP-1 复合物通过隔离 cAMP 反应元件蛋白 (CRE) 结合蛋白 (CBP) 辅激活剂对 5-氨基乙酰丙酸合酶基因表达的抑制作用*
DOI：
10.1074/jbc.m205057200
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
E. Cánepa
中科院分区：
文献类型：
--
作者：
Alejandra S. Guberman;M. E. Scassa;L. Giono;C. Varone;E. Cánepa
激活蛋白-1（AP-1）转录因子是参与多种转录调控过程的早期反应基因。佛波酯12-O-十四酰基佛波醇-13-乙酸酯（TPA）常用于诱导AP-1活性。本研究的目的是探讨TPA调控血红素生物合成的第一步和速率控制步骤5-氨基乙酰丙酸合成酶（ALAS）基因表达的分子机制。先前对ALAS 5′侧翼序列的分析揭示了基础表达和cAMP刺激表达所需的两个cAMP反应元件（CRE）的存在。将大鼠ALAS基因5′侧翼区的-833至+42片段亚克隆到氯霉素乙酰转移酶（CAT）报告载体中。瞬时转染HepG 2人肝癌细胞后，pALAS/CAT表达载体可产生明显的CAT活性，但TPA可抑制CAT活性。序列和缺失分析检测到一个TPA反应元件（TRE），位于-261和-255（TRE-ALAS）之间，这对TPA调控至关重要。我们证明，c-Fos，c-Jun，和JunD参与TPA抑制作用，由于他们的能力，结合TRE-ALAS，证明了超位移分析和他们的能力，在转染试验中抑制启动子活性。当CRE蛋白结合蛋白或p300异位表达时，TPA治疗或Fos/Jun过表达对ALAS启动子活性的抑制在很大程度上得到缓解。当TRE位点相对于CRE位点被置于不同的环境中时，它似乎充当转录增强子。我们建议，在TPA的存在下观察到的ALAS基础活性的降低可能反映了该启动子组装生产性的前起始复合物的能力较低，由于CRE蛋白结合蛋白螯合。我们还建议，这个AP-1网站的转录特性将取决于一个空间的处置依赖的方式相对于CRE网站和转录起始位点。
Activation protein-1 (AP-1) transcription factors are early response genes involved in a diverse set of transcriptional regulatory processes. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) is often used to induce AP-1 activity. The purpose of this work was to explore the molecular mechanisms involved in the TPA regulation of ubiquitous 5-aminolevulinate synthase (ALAS) gene expression, the first and rate-controlling step of the heme biosynthesis. Previous analysis of the 5′-flanking sequence of ALAS revealed the existence of two cAMP-response elements (CRE) required for basal and cAMP-stimulated expression. The fragment −833 to +42 in the 5′-flanking region of rat ALAS gene was subcloned into a chloramphenicol acetyltransferase (CAT) reporter vector. The expression vector pALAS/CAT produced a significant CAT activity in transiently transfected HepG2 human hepatoma cells, which was repressed by TPA. Sequence and deletion analysis detected a TPA response element (TRE), located between −261 and −255 (TRE-ALAS), that was critical for TPA regulation. We demonstrated that c-Fos, c-Jun, and JunD are involved in TPA inhibitory effect due to their ability to bind TRE-ALAS, evidenced by supershift analysis and their capacity to repress promoter activity in transfection assays. Repression of ALAS promoter activity by TPA treatment or Fos/Jun overexpression was largely relieved when CRE protein-binding protein or p300 was ectopically expressed. When the TRE site was placed in a different context with respect to CRE sites, it appeared to act as a transcriptional enhancer. We propose that the decrease in ALAS basal activity observed in the presence of TPA may reflect a lower ability of this promoter to assemble the productive pre-initiation complex due to CRE protein-binding protein sequestration. We also suggest that the transcriptional properties of this AP-1 site would depend on a spatial-disposition-dependent manner with respect to the CRE sites and to the transcription initiation site.
佛波酯诱导人 CYP1A2 增强剂。
DOI：
10.1006/abbi.1997.0491
发表时间：
1998
期刊：
Archives of biochemistry and biophysics.
影响因子：
--
作者：
Quattrochi,LC;Shih,H;Pickwell,GV
通讯作者：
Pickwell,GV
影响因子：
14.5
作者：
Saatcioglu,F;Claret,FX;Karin,M
通讯作者：
Karin,M
蛋白激酶 C 在胰岛素调节 c-fos 转录中的作用。
DOI：
--
发表时间：
1992
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Messina,JL;Standaert,ML;Ishizuka,T;Weinstock,RS;Farese,RV
通讯作者：
Farese,RV