Functions of proto-oncogenes in a normal cell Viral oncogene originates from cellular gene.

Outline Since 1981, cancer has been the leading cause of death among the Japanese. One of four people dies of cancer. What is the mechanism behind the development of cancer? In recent years, remarkable advances in molecular biology have shown that the transformation of normal cells to cancer cells is mediated by two kinds of genes: oncogenes, which promote aggressive cell proliferation, and tumor suppressor genes, which are associated with the inhibition of abnormal cell growth and with apoptosis, a programmed cell death. Irregularities of these genes can affect normal body organization, resulting in the destruction of healthy lives. Genes associated with oncogenesis often produce proteins that play important roles in transmitting external signals to the inside of cells. If an abnormality occurs in any one of these proteins, cells become unable to exhibit normal functions, such as proliferation and differentiation, which in turn leads to the development of cancer. Exploring how such oncogene products derange cellular signal transduction is therefore expected to provide very valuable information about the process of regulation in normal cells, a problem that has long been posed in cellular biology. Focusing on genes involved in the signal transduction pathway, especially oncogenes encoding tyrosine kinases and adapterproteins, which mediate the interaction of signal molecules, the research activities at this department are directed to elucidate how these oncogene products generate the signals leading to the oncogenic transformation at the molecular level. Research Activities It is well known that "oncogenes" are produced due to mutations in normal cellular genes (proto-oncogenes). We have investigated the Crk protein to reveal how this protein leads to cellular functional abnormalities and oncogenesis. This protein was first discovered as a product of a chicken cancer virus. Triggered by our research into the Crk protein, studies have clarified its structural components now known as the SH2 and SH3 domains. SH2 has been shown to bind to a phosphorylated tyrosine residue in protein, whereas SH3 has been shown to bind to a peptide having a proline-rich sequence. With such properties, these domains can mediate and promote the interaction of proteins involved in signal transduction. The Crk protein, unlike other oncogene products, has a quite simple structure comprising SH2 and SH3 only. Our research activities aim at elucidating the mechanism by which this simple structure protein changes the cellular signal transduction mechanism and eventually transforms normal cells into cancer cells. To this end, we utilize not only the chicken embryo fibroblasts, the original target cell for this oncogene product, but also Drosophila, a fruit fly that permits genetic analysis of the signal transduction mechanism. We have already found that this protein exhibits a very unique action of inducing the phosphorylation of particular proteins in cells. By accurately understanding the functions of the two domains SH2 and SH3, we will elucidate the novel mechanism of oncogenesis by adapter proteins lacking enzyme activity and hopefully establish novel countermeasures against cancer. Subjects Investigation of the mechanism of oncogenesis by an adapter type oncogene product Crk. Genetic analyses of Crk and Crk-binding factors using Drosophila. Analysis of signal transduction pathways mediated by c-CrkII. Investigation of the process of leukemogenesis by nonreceptor type tyrosine kinase c-Abl. Studies on the molecular mechanism of human cells resisting to oncogene