LATE SIGNALS ARE REQUIRED FOR THE STIMULATION OF DNA-SYNTHESIS IN RATMAMMARY FIBROBLASTS BY GROWTH-FACTORS

Maximal stimulation of DNA synthesis in quiescent rat mammary (Rama) 2 7 fibroblasts is elicited by epidermal growth factor (EGF) or basic fi broblast growth factor (bFGF) 18 h after the initial addition of the g rowth factors-the 'lag' period. At maximally-stimulating concentration s, EGF and bFGF are interchangeable 9 h after their initial addition. When the initial concentration of growth factor is below that required to elicit a maximal response, it is possible to increase the level of DNA synthesis by increasing the concentration of growth factor 9 h af ter its initial addition. When the initial concentration of growth fac tor is high, substitution by a lower concentration of growth factor af ter 9 h allows a greater proportion of cells to synthesize DNA than wo uld be expected from a continuous low dose of growth factor. Similar r esults are obtained when both the growth factor and its concentration are changed 9 h after the initial addition of growth factor. However, when EGF at a low concentration is substituted for a high concentratio n of EGF or bFGF the resulting increase in the levels of DNA synthesis is greater when EGF rather than bFGF is added for a second time. The half-life of the growth-stimulatory signals delivered by EGF and by bF GF 9 h after their initial addition is 1-2 h. These results suggest th at to stimulate DNA synthesis: (i) EGF or bFGF must deliver a signal(s ) continuously; (ii) the initial signals produced by EGF and bFGF are equivalent; (iii) the signals produced between 9-18 h by EGF may be di fferent to those produced by bFGF.