Adenosine 3′, 5′-Monophosphate and Histone Phosphorylation during Enzyme Induction by Glucagon in Rat Liver

A single intraperitoneal injection of glucagon to rat leads, within 5 min, to a 30-fold increase in the concentration of adenosine 3′, 5′-monophosphate (cyclic AMP)* in liver. The high level of cyclic AMP drops rapidly, returning to the original level after 90min. Induction of liver tyrosine aminotransferase [EC 2.6.1.5] occurs at 30 min following administration of the hormone and the high level of enzyme activity remains for 2hr and then gradually decreases. During the enzyme induction, lysinerich (F1) histone among nuclear proteins is only a detectable protein whose phosphorylation is significantly stimulated. Kinetic studies indicate that the phosphorylation of a specific site of histone F1 precedes the induction of tyrosine aminotransferase, and that the rate of this phosphorylation is proportional to the intracellular cyclic AMP concentration. Protein kinase [EC 2.7.1.37] activity, which is measured in vitro without adding cyclic AMP, increases at 5 min and returns to the control level at 75 min. Tryptic phosphopeptides obtained from histone F1 preparations, which are phosphorylated in vivo and in vitro, are electrophoretically identical. These results confirm that histone F1 serves as a substrate in vivo for cyclic AMP-dependent protein kinase.