Analysis of transcrition regulators involved in intracellular signaling

参与细胞内信号转导的转录调节因子分析

• 批准号: 08670159
• 负责人: MAEKAWA Toshio
• 金额: $ 1.41万
• 依托单位: The Institute of Physical & Chemical research (RIKEN)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670159/
• 关键词: transcriptional control; knockout mouse; signal transduction; cAMP pathway; CRE-BP1; ATF-2; 転写因子; 胎便吸入症候群

A number of transcription factors of ATF/CREB family have been identified so far. This group of proteins contains the DNA-binding domain consisting of the cluster of basic amino acids and the leucine zipper, so-called b-zip. Among many transcription factors of ATF/CREB family, three factors, CRE-BP1 (also called ATF-2), ATF-a, and CRE-BPa forms a subgroup. This group of factors forms a homodimer or heterodimer with c-Jun, and binds to CRE.The stress-activated kinases (SAPK) such as Jun amino-terminal kinase (JNK) and p38 phosphorylates this group of factors at the sites close to the N-terminal transcriptional activation domain, and stimulate their trans-activating capacity. Since a group of factors of the ATF/CREB family including CREB are activated via direct phosphorylation by cAMP-dependent protein kinase (PKA), these two groups of factors are linked to the distinct signaling cascades, PKA and SAPK pathways.To investigate the physiological role od CRE-BP1 genefamly, we made the knockout mice of CRE-BP1, CRE-BPa, and ATF-a genes. The mouse null mutant of CRE-BP1 died shortly after birth with symptoms of severe respiratory distress, and that the mutant lung was filled with meconium like human meconium aspiration syndrome (MAS) which is a common neonatal problem. The decreased trophobalst proliferation in the mutant placenta and the occurrence of hypoxia in the mutant embryos were observed at 18.5 dpc. Anomalies in placenta may cause the insufficient oxgen supply followed by gasping respirations and aspiration of the amniotic fluid containing meconium. The expression level of PDGF receptor alpha gene which plays an important role for proliferation of trophoblast, was found to be decreased in the trophoblasts of mutant placenta. The CRE-BP1 null mutants will be useful to understand the mechanisms of MAS and to develop the therapy for MAS.

目前已鉴定出多种ATF/CREB家族转录因子。这组蛋白质含有由碱性氨基酸簇和亮氨酸拉链（即所谓的 b-zip）组成的 DNA 结合结构域。在ATF/CREB家族的众多转录因子中，CRE-BP1（也称为ATF-2）、ATF-a和CRE-BPa这三个因子组成一个亚组。该组因子与c-Jun形成同二聚体或异二聚体，并与CRE结合。Jun氨基末端激酶（JNK）和p38等应激激活激酶（SAPK）在靠近c-Jun的位点磷酸化该组因子。 N端转录激活结构域，并刺激其反式激活能力。由于 ATF/CREB ​​家族的一组因子（包括 CREB）是通过 cAMP 依赖性蛋白激酶（PKA）直接磷酸化而激活的，因此这两组因子与不同的信号级联、PKA 和 SAPK 途径相关。为了研究CRE-BP1基因家族的作用，我们制作了CRE-BP1、CRE-BPa和ATF-a基因的敲除小鼠。 CRE-BP1无效突变小鼠在出生后不久死亡，并出现严重呼吸窘迫的症状，突变体肺部充满胎便，类似于人类胎便吸入综合症（MAS），这是一种常见的新生儿问题。在18.5 dpc时观察到突变胎盘中滋养层增殖减少以及突变胚胎中缺氧的发生。胎盘异常可能会导致氧气供应不足，导致喘息和吸入含有胎便的羊水。在突变胎盘的滋养层细胞中，发现对滋养层增殖起重要作用的PDGF受体α基因的表达水平降低。 CRE-BP1 无效突变体将有助于理解 MAS 的机制和开发 MAS 的治疗方法。