In continuing efforts to elucidate the mechanism of pathogenesis of neoplasia using the N-nitroso tumor model, this proposal deals with modulation of the transformed state in anaplastic glioma cell line T9 established from one of the N-nitrosourea-induced tumors. Nerve growth factor (NGF) and glia maturation factor (GMF) have been found to induce changes of growth pattern as well as morphological differentiation of T9 cells in culture. This system will be utilized in this project to gain understanding of the mechanisms of NGF and GMF actions, which may provide the basis for the potential use of these physiological factors as reverse transforming agents in cancer therapy. The role of second messengers and their balance in reverse transformation will be studied by examining effects of bromo- cAMP, 1-oleoyl-2-acetylglycerol, 12-tetradecanoylphorbol-13- acetate, and Ca ionophore as well as effectors of second messenger production such as cholera toxin, forskolin and phosphatidic acid on growth differentiation of T9 cells. Expression of the cellular src gene and synthesis and phosphorylation of the src gene product as affected by NGF and GMF as well as various second messengers will be investigated in order to determine the relationship between reverse transformation of T9 cells and this gene product which is known to be closely associated with neural differentiation. Synthesis and phosphorylation of tubulin, intermediate filament proteins, actin and their associated proteins will be examined in T9 cells during exposure to NGF and GMF as well as various second messengers. Attempts will then be made to correlate changes in subcellular organization of cytoskeletons with NGF- and GMF-induced morphological differentiation.
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