This grant proposal has focused, and will continue to focus, on the general problem of the relationship of the mechanisms of cell differentiation to the mechanisms of tumorigenesis. The notion that the intracellular controls regulating the emergence of a normal, definitive muscle cell, or cartilage cell, or pigment cell, etc., when malfunctioning may yield instead a """"""""neoplastic"""""""" cell has been discussed since Boveri's time over 60 years ago. The theoretical assumption is that those mechanisms shifting normal embryonic cells from one compartment to the next in a given lineage are those mechanisms that """"""""transform"""""""" normal cells into neoplastic cells. Our own approach has focused on (1) transforming chick myogenic, chondrogenic and melanogenic cells with a temperature-sensitive Rous sarcoma mutant, and monitoring the metabolic responses of such cells at permissive and non-permissive temperatures, and (2) monitoring the metabolic responses of the same cell types reared in the co-carcinogen, phorbol-12-myristate-13-acetate (PMA). We have found that ts-transformed myogenic, chondrogenic and melanogenic cells at permissive temperature continue to replicate as """"""""transformed cells"""""""": they do not terminally differentiate. If however, such transformed cells are shifted to non-permissive temperature, they terminally differentiate into myotubes, chondroblasts, and melanoblasts, respectively. Similarly, PMA reversibly arrests the differentiation of myogenic, chondrogenic and melanogenic cells.
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