ISOLATION OF NOVEL ONCOGENES BY AN EFFICIENT EXPRESSION CLONING SYSTEM

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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.