MOLECULAR MECHANISMS OF MULTI-STAGE CARCINOGENESIS

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The experimental approach to understanding the molecular basis of multistage carcinogenesis focuses on unraveling the puzzle of how cellular regulation occurs in the presence of multiple influences. As such the results will uniquely complement studies of components of signal transduction paths done largely in isolation of the many other facets of cellular regulation. The primary points of this investigation are the signal transducing enzyme protein kinase C (PKC), also known to be the receptor for tumor promoting phorbol esters, and proteins encoded by oncogenes that have demonstrated roles in intracellular signal transduction, such as src, ras, raf, mye, and jun. A molecular approach will be used to modify the signal transducing apparatus of mouse embryo C3H 10T1/2 cells and to analyze the effects of these cellular phenotype. Since the major subject of this investigation is signal transduction mediated by PKC a large segment of the effort is to be put into understanding the biochemistry of PKC function and regulation as well as to learn more about the molecular and cellular biology of PKC. The interactions of multiple elements of cellular signal transduction will be investigated at the same time. One of the goals is to combine these separate data to develop a better idea of the molecular apparatus in cells that integrates the transduced extracellular signals to yield a single outcome. It is probable that resistance of some cells and strains of mice to tumor promoting agents such as phorbol esters involves alterations in the integrative apparatus making study of such resistant cells useful. Lastly, somatic cell genetics system will be developed for investigating the transcytoplasmic phase of cellular signal transduction that begins with PKC and ends with activation of gene transcription. The latter study, together with the information that will be obtained about the interactions of signal transduction, will make it possible to obtain a more complete understanding of the process of cellular signal transduction and how it is involved in multistage carcinogenesis.