Activation of the human histamine H2 receptor is linked to cell proliferation and c- fos gene transcription.

We examined whether histamine could regulate cell proliferation and expression of the early response gene c- fos in HEK-293 cells stably transfected with the human H2receptor (HEK-H2). Histamine stimulated [3H]thymidine incorporation [50% effective concentration (EC50) = 3.6 × 10-6 M] in HEK-H2 cells in a cimetidine-sensitive manner and increased c- fos mRNA in a time-dependent fashion, reaching maximal induction after 30 min. Histamine induced luciferase activity in HEK-H2cells transiently transfected with a construct containing the luciferase reporter gene ( Luc) coupled to the serum response element (SRE) of the c- fos gene promoter (EC50 = 1.5 × 10-6 M) or a plasmid containing the SRE core fragment (bases -320 to -298). The protein kinase C (PKC) inhibitor staurosporine and long-term pretreatment of HEK cells with phorbol ester inhibited the effect of histamine on PKC activation, SRE- Lucactivity, and [3H]thymidine incorporation. We have demonstrated that activation of the human H2 receptor can lead to induction of c- fos gene transcription and cell proliferation through a PKC-dependent mechanism.