Classification system based on the functional equivalency of mitogens that regulate WI-38 cell proliferation

Analysis of the proliferative response of WI-38 cells to nine mitogens, which in various specific combinations stimulate DNA synthesis in these cultures, delineated three classes of mitogens. Class I includes epidermal growth factor (EGF), fibroblasts growth factor (FGF), platelet-derived growth factor (PDGF), and thrombin (THR); Class II includes insulin-like growth factor I (IGF-I), multiplication stimulating activity (MSA) (the rat homolog of human IGF-II), and insulin; and Class III includes hydrocortisone (HC) or the synthetic analog dexamethasone (DEX). In cultures arrested at low density, members of each of the three classes act synergistically in stimulating DNA synthesis. Any Class I mitogen in combination with any Class II and either Class III mitogen stimulated DNA synthesis of levels observed in 10% serum-supplemented medium. At least some (EGF, FGF, PDGF) and possibly all (THR) of the Class I mitogens are known to act through separate receptor systems. Our experiments using blocking antibodies to the IGF-I receptor confirm that the Class II mitogens all act by binding to IGF-I receptors. Use of the inhibitory synthetic glucocorticoid analog RU 486 confirmed that the Class III mitogens act via the glucocorticoid receptor. Thus, growth factor-induced DNA synthesis in WI-38 cells is apparently mediated by the glucocorticoid receptor (Class III), the IGF-I receptor (Class II), and most interestingly any one of several Class I growth factor receptors.