Thomas D. Gelehrter

Lethal Neonatal Deficiency of Carbamyl Phosphate Synthetase

Abstract A male infant, who appeared normal at birth, manifested hypothermia, irritability, and hypertonia 24 hours after beginning protein feedings. Increasing rigidity and coma ensued, and the ch...

Mechanisms of hormonal induction of enzymes

Abstract The study of enzyme induction by hormones has provided an important experimental model for the investigation of both the molecular mechanisms of hormone action as well as the regulation of specific gene expression in higher organisms. The exact mechanisms by which hormones induce enzymes are as yet unknown. The ability to study enzyme induction in relatively simple experimental systems such as cells in tissue culture allows the investigator to assess unequivocally the role of single hormones and to pose mechanistic questions. It is hoped that advances in genetic approaches to enzyme induction will accelerate progress in understanding these mechanisms. Studies of tyrosine aminotransferase induction by glucocorticoids in the HTC cell system have led to a model of enzyme induction in which the inducing steroids are thought to antagonize the action of a posttranscriptional repressor. The emphasis of this model, in contrast to those based on bacterial models, is that regulation of specific gene expression need not operate at the genetic or transcriptional level; i.e., by stimulating specific mRNA synthesis. Transcripitonal controls surely exist in animal cells, but their role in specific enzyme induction remains to be established. In addition to glucocorticoids, several other hormonal factors including insulin, a macromolecular factor in serum, and dibutyryl cyclic-AMP, can also enhance TAT synthesis, all probably affecting separate and distinct posttranscriptional steps in the synthesis of a single protein.

Induction of tyrosine aminotransferase by Sepharose-insulin.

Abstract Insulin covalently bound to Sepharose causes a nearly 2-fold increase in tyrosine aminotransferase activity in monolayer cultures of hepatoma cells previously incubated with dexamethasone. The time course of the induction and its resistance to inhibition by actinomycin D is similar to that obtained with free insulin, although approximately 100 times higher concentrations of Sepharose-insulin than free insulin are required to achieve the same stimulation. Control experiments demonstrated that 0.2–2% of the bound insulin is released from the Sepharose during incubation with the cells. Because of the much greater sensitivity of the hepatoma cells to free insulin, however, this is sufficient to account for the majority of the stimulatory effect of Sepharose-insulin on transaminase activity. Our data do not exclude the hypothesis that insulin bound to Sepharose stimulates tyrosine aminotransferase activity in HTC cells, but do indicate the need for caution in the use of insoluble derivatives of insulin to determine whether insulin can exert its effects on specific protein synthesis without entering the cell.

Variable expression of Marfan syndrome in monozygotic twins

A pair of monozygotic twins with the Marfan syndrome with variable expression is presented. One of the twins, in addition to more severe musculoskeletal and ocular manifestations, had coarctation of the aorta as the cardiovascular manifestation of this syndrome. Analysis of red cell antigens, serum proteins and dermatoglyphic examination suggests a high probability of monozygosity. Accordingly, the variation in expression of this autosomal dominant disorder between the twins is most likely due to the modifying influences of environmental factors. Also noteworthy is the fact that the resected coarctation tissue domonstrated the histopathologic changes characteristic of cystic medial necrosis, and thus served as an additional piece of evidence supporting the diagnosis of the Marfan syndrome. This was of particular importance in view of the absence of any family history of this syndrome and the absence of ectopia lentis or the more typical cardiovascular manifestations in either twin.

MOLECULAR FORMS OF HEPATIC TYROSINE AMINOTRANSFERASE ACTIVITY

ABSTRACT. Dexamethasone, insulin, and serum induce an additive increase in the activity of tyrosine aminotransferase in hepatoma cells in tissue culture. By the criteria of immunotitration, heat stability, and electrophoresis on polyacrylamide gels, we have shown previously that all three effectors increase the cellular concentration of the same protein. During the course of these studies, however, we observed an apparent isozyme of tyrosine aminotransferase whose activity is not enhanced by these three inducers.