ACTIVATION OF THE HUMAN HISTAMINE H-2-RECEPTOR IS LINKED TO CELL-PROLIFERATION AND C-FOS GENE-TRANSCRIPTION

We examined whether histamine could regulate cell proliferation and ex pression of the early response gene c-fos in HEK-293 cells stably tran sfected with the human H-2 receptor (HEK-H-2). Histamine stimulated [H -3]thymidine incorporation [50% effective concentration (EC50) = 3.6 X 10(-6) M] in HEK-H-2 cells in a cimetidine-sensitive manner and incre ased c-fos mRNA in a time-dependent fashion, reaching maximal inductio n after 30 min. Histamine induced luciferase activity in HEK-H-2 cells transiently transfected with a construct containing the luciferase re porter gene (Luc) coupled to the serum response element (SRE) of the c -fos gene promoter (EC50 = 1.5 X 10(-6) M) or a plasmid containing the SRE core fragment (bases -320 to -298). The protein kinase C (PKC) in hibitor staurosporine and long-term pretreatment of HEK cells with pho rbol ester inhibited the effect of histamine on PKC activation, SRE-Lu c activity, and [H-3]thymidine incorporation. We have demonstrated tha t activation of the human H-2 receptor can lead to induction of c-fos gene transcription and cell proliferation through a PKC-dependent mech anism.