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.

目前已鉴定出许多ATF/CREB家族的转录因子。这组蛋白质包含由碱性氨基酸簇和亮氨酸拉链（所谓的b-zip）组成的DNA结合结构域。在ATF/CREB家族的许多转录因子中，CRE-BP 1（也称为ATF-2）、ATF-α和CRE-BPa三个因子形成一个亚群。应激激活激酶（SAPK）如Jun氨基末端激酶（JNK）和p38等可使这组因子在靠近N端转录激活结构域的位点磷酸化，从而激活其反式激活能力。由于包括CREB在内的ATF/CREB家族的一组因子是通过cAMP依赖性蛋白激酶（PKA）直接磷酸化而被激活的，这两组因子与不同的信号级联途径PKA和SAPK通路相关。CRE-BP 1的小鼠无效突变体在出生后不久死亡，具有严重呼吸窘迫的症状，并且突变体肺充满胎粪，如人胎粪吸入综合征（MAS），这是常见的新生儿问题。在18.5 dpc时，突变体胎盘中滋养层增殖减少，突变体胚胎中出现缺氧。胎盘异常可引起氧气供应不足，继而出现喘息和吸入含胎粪的羊水。在突变型胎盘滋养细胞中，对滋养细胞增殖起重要作用的PDGF受体α基因的表达水平被发现降低。CRE-BP 1缺失突变体的发现将有助于进一步了解MAS的发病机制，并为MAS的治疗提供新的思路。

项目成果

Tanaka, Y.et al.: "Abnormal skeletal patterning in embryos lacking a single Cbp allele:a partial similarity with Rubinstein-Taybi syndrome." Proc.Natl.Acad.Sci.USA. 94. 10215-10220 (1997)

Tanaka, Y. 等人：“缺乏单个 Cbp 等位基因的胚胎中的异常骨骼模式：与 Rubinstein-Taybi 综合征部分相似。”

Tanaka,Y.et al.: "Abnormal skeletal patterning in embryos lacking a single Cbp allele : a partial similarity with Rubinstein-Taybi syndrome." Proc.Natl.Acad.Sci.USA. 94. 10215-10220 (1997)

Tanaka,Y.et al.：“缺乏单个 Cbp 等位基因的胚胎中的异常骨骼模式：与 Rubinstein-Taybi 综合征部分相似。”

Tanaka, Y., Naruse, I., Maekawa, T., Masuya, H., Shiroishi, T.& Ishii, S.: "Abnormal skeletal patterning in embryos lacking a single Cbp allele : a partial similarity with Rubinstein-Taybi syndrome." Proc.Natl.Acad.Sci.USA. 94. 10215-10220 (1997)

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