Modulation of cellular signaling mechanisms by qualitative differences in dietary proteins and their metabolites were studied at the level of: A. Iminopeptides B. Release of pyrroline 5-carboxylate (P5C), and C. Effect of pyrroline 5-carboxylate on mitogenesis. A. Iminodipeptides. Dipeptides containing proline or hydroxyproline circulate in plasma and are delivered to tissues where they are hydrolyzed by prolidase. Using a proline-auxotrophic cell line, we showed that a variety of iminodipeptides could satisfy the proline requirements for growth. This is the first demonstration that iminodipeptides can serve as the sole source of proline. B. Release of pyrroline 5-carboxylate. Previous work showed that P5C circulates in human plasma. In cultured human fibroblasts, P5C is released into the medium. The rate of accumulation is markedly increased by serum insulin and insulin-like growth factor-1 but not by platelet-derived growth factor. Thus, the production and/or release of P5C is under hormone control. C. Effect of pyrroline 5-carboxylate on mitogenesis. P5C stimulates PRPP and purine ribonucleotide synthesis synergistically with platelet-derived growth factor. It also increases the incorporation of thymidine in serum- activated cells. Inhibitor studies suggest that the effect is due to the production of inositol phosphates. The significance of the project is to elucidate the mechanisms by which qualitative differences in dietary proteins relate to cancer cause and prevention either as an independent mechanism or as a mechanism adjunctive to dietary fat and/or total caloric intake.
