Operation of pleiotropic control in hormonal regulation and in neoplasia

The purpose of this work was to evaluate the experimental evidence that suggests that an examination of the biochemical phenotypes in differentiation, hormonal regulation and neoplasia leads to the assumption of the operation of pleiotropic controls. Evidence for pleiotropic control mechanisms was provided in carbohydrate metabolism by analysis of the phenotype as revealed in the behavior of opposing key enzymes in differentiation, under endocrine conditions such as diabetes and insulin administration and in liver neoplasia. Evidence for pleiotropic control mechanisms in nucleic acid metabolism was provided by examination of post-natal liver differentiation, hepatic regeneration and neoplasia. The behavior of opposing key enzymes and metabolic pathways involved in the de novo and salvage pathways of DNA metabolism was compatible with the suggestion for the operation of pleiotropic controls. Evidence for operation of pleiotropic control mechanisms was also obtained in studies of cAMP metabolism. The evidence here came from investigation of the antagonistic behavior of opposing enzymes of cAMP metabolism in the spectrum of liver tumors of different growth rates. In these hepatomas the activity of the membrane cAMP phosphodiesterase increased, whereas concurrently the activity of adenylate cyclase decreased in parallel with the increase in tumor growth rate. The ratios of the activities of cAMP phosphodiesterase/adenylate cyclase exhibited a positive correlation with the growth rate of liver tumors. This metabolic imbalance should make the metabolic pattern unfavorable for the production of cAMP in the plasma membrane of liver tumors. The imbalance in hepatomas appeared specific to neoplasia because no similar alterations were observed in the regenerating or in the differentiating liver. The operation of pleiotropic controls in pentose phosphate metabolism was also observed by examining the behavior of four enzymes, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, transaldolase and transketolase. The activities of the four enzymes decrease in diabetes and insulin administration restores the activities to normal range. During differentiation the four enzymes exhibit an upward swing towards the levels observed in the liver of adult rats. Glucose-6-phosphate dehydrogenase and transaldolase were increased in all hepatomas examined. The other two enzymes showed no relationship to hepatoma growth rate. The role of the four enzymes that may play key roles in pentose phosphate metabolism was discussed in relation to the production of NADPH and the biosynthesis of ribose-5-phosphate. The regulatory levels in the expression of pleiotropic changes in the reprogramming of gene expression were discussed. The conclusion was drawn that pleiotropic regulation would require the operation at the genetic level of pleiotropic genes (master genes or integrative genes). At the epigenetic level it was postulated that groups of mRNAs specifying different structural information for various enzymes would carry common recognition sites that may result in the preferential translation or degradation. Both genetic and epigenetic mechanisms may provide for the expression of genetic information that is manifested at the phenotypic level of pleiotropic effects.