ISOLATION OF NOVEL ONCOGENES BY AN EFFICIENT EXPRESSION CLONING SYSTEM

利用高效的表达克隆系统，几个新的癌基因 从不同的组织和细胞系中分离得到。通过分析这些 癌基因、恶性转化的信号转导途径 正在被澄清。今年的主要发现如下：(1)A 从小鼠睾丸中分离出转化基因，发现其编码一种 成纤维细胞生长因子家族的生长因子(成纤维细胞生长因子8)； 主要在胚胎组织中表达，而在成人组织中不表达，除非 睾丸。人成纤维细胞生长因子-8基因定位于染色体 10.(2)癌基因OST下游的信号转导通路 利用该系统分离得到的菌株，得到了明确的结果。OST激活了一个 小的GTP结合蛋白，CDC42，进而激活一种蛋白质 激酶级联、应激激活蛋白激酶(SAPK)或c-jun氨基- 末端激酶(JNK)途径。(3)ect2的染色体定位 而Tim，以前使用这个系统分离的癌基因，有 分别被确定为3q26.1-q26.2和7q33-q35；其中 常见的染色体重排在人类恶性肿瘤中被报道。 (4)小眼炎转录因子(MITF)，人类的同源物 克隆了小鼠小眼症基因。MITF的异位表达 NIH/3T3细胞诱导细胞形态改变，但MITF 转染体在裸鼠体内未诱发肿瘤。有趣的是，MITF- 诱导灶含有黑素细胞样细胞，具有树突状突起。 这些细胞还表达黑素生成标记，表明MITF是 参与黑素细胞分化。

Using an efficient expression cloning system, several novel oncogenes were isolated from various tissues and cell lines. By analyzing these oncogenes, signal transduction pathways for malignant transformation are being clarified. The main findings this year are as follows: (1) A transforming gene was isolated from mouse testis and found to encode a growth factor of the fibroblast growth factor family (FGF-8); and it is mainly expressed in embryonic tissues but not in adult tissue, except testis. The location of the human FGF-8 gene was mapped to chromosome 10. (2) A signal transduction pathway downstream from ost, an oncogene that was isolated using this system, was clarified. Ost activates a small GTP-binding protein, Cdc42, and in turn it activates a protein kinase cascade, stress-activated protein kinase (SAPK) or c-Jun amino- terminal kinase (JNK) pathway. (3) The chromosomal locations of ect2 and TIM, oncogenes that were isolated using this system previously, have been determined to be 3q26.1-q26.2 and 7q33-q35, respectively; where common chromosomal rearrangements were reported in human malignancies. (4) microphthalmia transcription factor (MITF), the human homolog of the mouse microphthalmia gene, was cloned. Ectopic expression of MITF in NIH/3T3 cells induced morphologically altered cells, but MITF transfectants did not induce tumors in nude mice. Interestingly, MITF- induced foci contain melanocyte-like cells with dendritic processes. These cells also expressed melanogenic markers, indicating that MITF is involved in melanocyte differentiation.