TETRAHYDROBIOPTERIN AS A MEDIATOR OF PC12 CELL-PROLIFERATION INDUCED BY EGF AND NGF

Epidermal growth factor and nerve growth factor increased the prolifer ation of rat phaeochromocytoma PC12 cells through obligatory elevation of intracellular (6R)-tetrahydrobiopterin (BH4). Epidermal growth fac tor and nerve growth factor increased intracellular BH4 by inducing GT P-cyclohydrolase, the rate-limiting enzyme in BH4 biosynthesis. Specif ic inhibitors of BH4 biosynthesis prevented growth factor-induced incr eases in BH4 levels and proliferation. The induction of GTP cyclohydro lase, BH4 and cellular proliferation by nerve growth factor was mediat ed by cAMP. Elevation of BH4 biosynthesis occurred downstream from cAM P in the cascade used by nerve growth factor to increase proliferation . Thus, intracellular BH4 is an essential mediator of the proliferativ e effects of epidermal growth factor and nerve growth factor in PC12 c ells.