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

在1995年克隆了AT Motif Binding Factor 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被分离为甲胎蛋白（AFP）的转录控制因子，我们检测了ATBF1在几种产生AFP的胃癌中的表达水平。我们利用8种胃癌细胞库和一些临床病理，证明了ATBF1的缺失与胃癌中AFP基因的表达有关（Oncogene 2001,20:869-73）。我们还发现，ATBF1的缺失是AFP产生胃癌的一个明显特征，可能是其高度恶性性质的重要原因。接下来，我们以C2C12细胞为中胚层分化模型，对肌肉细胞的分化进行了研究。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成肌分化后，其表达水平下降。在C2C12细胞中强制表达ATBF1导致MyoD和myoggenin的表达受到抑制，Id3和cyclin D1的表达升高，从而在低血清状态下抑制成肌分化。我们认为ATBF1在维持未分化成肌细胞状态中起作用，其下调是启动C2C12细胞终末分化的先决条件。(生物。化学，2001,276:25057-25065)。从而阐明AFP产生胃癌的致癌转录机制及肌细胞分化的转录调控机制。

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.