Activation of guanyl cyclase and intracellular cyclic GMP by fibroblast growth factor

Abstract

THE induction of cell growth by animal serum in quiescent cultured fibroblasts is preceded by a sequence of regulated steps¹. These steps include stimulation of cellular transport systems¹, protein synthesis¹, ribosomal and tRNA synthesis² and eventually the induction of DNA synthesis followed by cell division^3,4. Two of the earliest changes observed after growth induction by serum are a transient increase in intracellular cyclic GMP⁵ (10-fold) and a decrease in cyclic AMP (two-to-threefold)^5,6,7. It has been suggested that cyclic GMP acts as a positive intracellular signal for cell growth since intracellular cyclic GMP concentrations showed an early transient increase upon growth induction by phytohaemagglutinin whereas no changes were observed in cyclic AMP concentrations⁸, and additions of high, non-physiological (10⁻⁶ to 10⁻⁴ M) concentrations of cyclic GMP can induce substantial increases in DNA synthesis in resting fibroblasts⁵. Recently a new polypeptide hormone, fibroblast growth factor (FGF), was isolated from bovine pituitary glands⁹. FGF in combination with the glucocorticoid, hydrocortisone, and a nonspecific carrier protein, bovine serum albumin (BSA), can completely replace exogenously added serum in bringing about all the steps leading to the initiation of DNA synthesis and cell division in some lines of BALB/c 3T3 cells¹⁰. Hydrocortisone, as it fails to initiate DNA synthesis alone in the absence of serum¹¹ is considered to potentiate the action of FGF⁹ (permissive effect).