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.

到目前为止，已经确定了ATF/CREB家族的许多转录因子。这组蛋白质包含由碱性氨基酸簇和亮氨酸拉链组成的DNA结合结构域，即所谓的B-ZIP。在ATF/CREB家族的许多转录因子中，有三个因素CRE-BP1（也称为ATF-2），ATF-A和CRE-BPA形成了亚组。这组因子与C-Jun形成同二聚体或异二聚体，并与CRE结合。应激激活激酶（SAPK），例如Jun氨基末端激酶（JNK）和p38磷酸化，在接近N-term末端转录激活能力和刺激其转换能力的位置上，这组因子磷酸化。由于包括CREB在内的ATF/CREB家族的一组因素是通过cAMP依赖性蛋白激酶（PKA）直接磷酸化激活的，因此这两个因素与不同的信号级联，PKA和SAPK途径有关。 CRE-BP1的小鼠无效突变体出生后不久死亡，患有严重呼吸窘迫的症状，突变肺充满了像人类胎粪吸入综合征（MAS）一样的胎粪（MAS），这是一个常见的新生儿问题。在18.5 dpc时观察到突变体胎盘中的滋养性降解和突变胚胎中缺氧的发生。胎盘中的异常可能会导致牛的供应不足，然后喘气呼吸和含有胎粪的羊水的抽吸。在突变体胎盘的滋养细胞中，发现PDGF受体α基因的表达水平在滋养细胞增殖中起重要作用。 CRE-BP1无效突变体将有助于了解MAS的机制并开发MAS的疗法。

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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Otuka, M., Fujita, M., Sugiura, Y., Yamamoto, T., Inoue, J., Maekawa, T., & Ishii, S.: "Synthetic inhibitors of regulatory proteins involved in the signaling pathway of the replication of human immunodeficiency virus 1." Bioorg.Med.Chem.5. 205-215 (1997)

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Otuka, M.et al.: "Synthetic inhibitors of regulatory proteins involved in the signaling pathway of the replication of human immunodeficiency virus 1." Bioorg.Med.Chem.5. 205-215 (1997)

Otuka, M.等人：“参与人类免疫缺陷病毒 1 复制信号通路的调节蛋白的合成抑制剂。”