An Early Cordycepin-Sensitive Event in the Action of Glucocorticoid Hormones on Rat Thymus Cells in vitro: Evidence that Synthesis of Mew Mrna Initiates the Earliest Metabolic Effects of Steroid Hormones

Abstract

Evidence is presented that the synthesis of poly A is essential for the progression of the sequence that follows binding of glucocorticoid hormones to nuclear receptor-complex and leads, after 20–30 min, to the well-known hormonal inhibition of glucose transport. Action of dexamethasone or cortisol on glucose is prevented by amounts of Cordycepin (3′deoxyadenosine) that rapidly block, by 40%, the appearance of poly A in polysomal fractions. Sensitivity to Cordycepin is limited to the first 10 min following hormone addition. In dose-response studies a parallelism is found between degrees of blockade of hormone action and blockade of poly A formation.

Studies of possible actions of Cordycepin on: binding of hormones to nuclear receptors, levels of ATP, and synthesis of protein, DNA and nuclear non-poly A RNA are all consistent with the interpretation that the antibiotic blocks hormone action either through its selective effects on poly A synthesis or disturbances in RNA metabolism related to reduced poly A synthesis, rather than through non-specific toxicity. An inhibition by Cordycepin of the emergence of rapidly-labelled RNase-sensitive RNA from the nucleus which parallels the inhibition of poly A synthesis may be such a disturbance.

These findings, coupled with previous results and with the known association between poly A and mRNA, suggest an involvement of a rapidly synthesized hormone-induced mRNA in the initiation of the rapidlyemerging metabolic effects of the glucocorticoid hormones. They also support the use of Cordycepin as a “probe” more specific than Actinomycin for the involvement of mRNA in the action of hormones.