The role of transcription factor ATBF1 for the expression of gastro intestinal phenotype in mucosal cells and gastro inestinal Cancer cells.

转录因子ATBF1在粘膜细胞和胃肠癌细胞表达胃肠表型中的作用。

基本信息

批准号：
13670542
负责人：
ITO Makoto
金额：
$ 2.3万
依托单位：
Nagoya city University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

After the cloning of AT Motif Binding Factor 1 (ATBF1) cDNA in 1995 we aimed to elucidate the ontogenesis and differentiation of a muscle and transcriptional carcinogenic mechanism in a digestive organ. Because ATBF1 was isolated as a transcriptional control factor of Alpha-fetoprotein (AFP), we examined the expression level of ATBF1 in several AFP producing gastric cancer. Using eight kinds of gastric cancer cell stocks and some clinical pathology, we demonstrated that the absence of ATBF1 is responsible for AFP gene expression in gastric cancer (Oncogene 2001, 20:869-73). We also revealed that the absence of ATBF1 is a distinct characteristic of AFP producing gastric cancer and might be important for its highly malignant nature. Next we studied about muscle cell differentiation with using the C2C12 cell which was a model of mesoderm differentiation. In vitro, ATBF1 was expressed in proliferating C2C12 myoblasts, but its expression levels decreased upon induction of myogenic differentiation in low serum medium. Forced expression of ATBF1 in C2C12 cells resulted in repression of MyoD and myogenin expression and elevation of Id3 and cyclin D1 expression, leading to inhibition of myogenic differentiation in low serum. We suggested that ATBF1 plays a role in the maintenance of the undifferentiated myoblast state, and its down regulation is a prerequisite to initiate terminal differentiation of C2C12 cells. (J. Biol. Chem. 2001, 276:25057-25065). So we elucidated the carcinogenic transcriptional mechanism of AFP producing gastric cancer and transcriptional regulation mechanism of muscle cell differentiation.

1995 年克隆 AT 基序结合因子 1 (ATBF1) cDNA 后，我们旨在阐明消化器官中肌肉的个体发生和分化以及转录致癌机制。由于 ATBF1 是作为甲胎蛋白 (AFP) 的转录控制因子被分离出来的，因此我们检测了 ATBF1 在几种产生 AFP 的胃癌中的表达水平。使用八种胃癌细胞库和一些临床病理学，我们证明 ATBF1 的缺失是胃癌中 AFP 基因表达的原因 (Oncogene 2001, 20:869-73)。我们还发现 ATBF1 的缺失是产生 AFP 的胃癌的一个显着特征，并且可能对其高度恶性的性质很重要。接下来，我们使用作为中胚层分化模型的C2C12细胞研究了肌细胞分化。在体外，ATBF1在增殖的C2C12成肌细胞中表达，但在低血清培养基中诱导肌原性分化后其表达水平降低。 C2C12细胞中ATBF1的强制表达导致MyoD和肌细胞生成素表达的抑制以及Id3和细胞周期蛋白D1表达的升高，从而抑制低血清中的肌原性分化。我们认为ATBF1在维持未分化成肌细胞状态中发挥作用，其下调是启动C2C12细胞终末分化的先决条件。 (生物化学杂志，2001，276：25057-25065)。因此我们阐明了AFP产生胃癌的致癌转录机制和肌细胞分化的转录调控机制。