Molecular mechanisms of retinoic acid-mediated control of cellular proliferation and differentiation

视黄酸介导的细胞增殖和分化控制的分子机制

• 批准号: 06807014
• 负责人: TAKIHARA Yoshihiro
• 金额: $ 1.28万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06807014/
• 关键词: F9; retinoic acid; 14-3-3; polyhomeotic; knockout mouse; レケノイン酸; ポリホメオティックタンパク質

By using the differential hybridization methods, we isolated the 20 kinds of cDNA clones, whose expression is induced during RA-mediated F9 cell differentiation. Focusing on the following two clones, we analyzed the structure and function of the genes.(1) Rae12 : the rae12 gene family encodes at least 5 kinds of different 14-3-3 protein members, whose expression is induced during RA-mediated F9 cell differentiation. We showed the expression of these members enhance the Raf-1 kinase. Furthermore, we demonstrated the following points : i) overexpression of 14-3-3 proteins enhances the signal transduction in the MAP kinase cascade, resulting in the stimulated cellular proliferation and tumorigenic transformation of NIH 3T3 cells. ii) the induced expression of 14-3-3 proteins enhances the signal transduction in the MAP kinase cascade, that plays an important role during RA-mediated F9 cell differentiation.(2) Rae28 : structure analysis the cDNA clone suggested that the rae28 gene is a mammalian homologue of a Drosophila polyhometic gene. We isolated the rae28 gene and established the rae28 knockout mice. The homozygotes are lethal and showed the following intriguing phenotypes : i) heart malformations, ii) ophthalmic abnormalities, iii) skeletal abnormalities (posterior transformation) , iv) cleft palate.

利用差异杂交技术，我们分离了20种在RA诱导F9细胞分化过程中表达的cDNA克隆。针对以下两个克隆，我们分析了基因的结构和功能。(1)Rae12：rae 12基因家族编码至少5种不同的14-3-3蛋白成员，其表达在RA介导的F9细胞分化过程中被诱导。我们发现这些成员的表达增强Raf-1激酶。此外，我们证明了以下几点：i）14-3-3蛋白的过表达增强了MAP激酶级联中的信号转导，导致NIH 3 T3细胞的刺激的细胞增殖和致瘤性转化。ii）14-3-3蛋白的诱导表达增强MAP激酶级联中的信号转导，其在RA介导的F9细胞分化期间起重要作用。(2)rae 28：结构分析cDNA克隆表明rae 28基因是果蝇多形基因的哺乳动物同源物。我们分离了rae 28基因并建立了rae 28基因敲除小鼠。纯合子是致命的，并显示出以下有趣的表型：i）心脏畸形，ii）眼科异常，iii）骨骼异常（后转化），iv）腭裂。

项目成果

M. Nomura,Y. Takihara,K. Shimada: "Isolation of a cDNA clone encoding mouse 3-hydroxyacyl CoA dehydrogenase" Gene. 160. 309-310 (1995)

M.野村，Y.

Z. Zou,M. Nomura,Y. Takihara,T. Yasunaga,K. Shimada: "Isolation and characterization of retinoic acid-inducible cDNA clones in F9 cells : A novel cDNA family encodes cell surface proteins sharing partial homology with MHC class I molecules" J. Biochem. (T

邹志明，M.

M.Nomura, Y.Takihara, K.Shimada: "Isolation of a cDNA clone encoding mouse 3-hydroxyacyl CoA dehydrogenase" Gene. 160. 309-310 (1995)

M.Nomura、Y.Takihara、K.Shimada：“编码小鼠 3-羟酰基 CoA 脱氢酶的 cDNA 克隆的分离”基因。

Nomura,M.,et al: "Isolation and characterization of retinoic acid-inducible cDNA clones in F9 cells-one of the early inducible clones encodes a novel protein sharing several highly homologous regious with a drosophila polyhomeotic protein" Differentiation

Nomura,M.,et al：“F9 细胞中视黄酸诱导型 cDNA 克隆的分离和表征 - 早期诱导型克隆之一编码一种与果蝇多同源异型蛋白共享多个高度同源区域的新蛋白”

Nomura,M.,et al: "One of the retinoic acid-inducible cDNA clones in mous embryonal carinoma F9 cells encodes a novel isoentyme of fructose 1,6-bisphosphatase" FEBS Letters. 348. 201-205 (1994)

Nomura,M.,et al：“小鼠胚胎癌 F9 细胞中视黄酸诱导的 cDNA 克隆之一编码果糖 1,6-二磷酸酶的新同工酶”FEBS Letters。