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 H2 receptor (HEK-H2). Histamine stimulated [3H]thymidine incorporation [50% effective concentration (EC50) = 3.6 x 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-H2 cells 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 x 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-Luc activity, 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.
Wang
L D
LD
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA.
Hoeltzel
M
M
Butler
K
K
Hare
B
B
Todisco
A
A
Wang
M
M
Del Valle
J
J
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002927:Cimetidine / Q000494:pharmacology*; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D017930:Genes, Reporter; D016762:Genes, fos; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007700:Kinetics; D008156:Luciferases / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D011970:Receptors, Histamine H2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection
D016760:Proto-Oncogene Proteins c-fos; D011970:Receptors, Histamine H2; D011993:Recombinant Fusion Proteins; D005576:Colforsin; D004815:Epidermal Growth Factor; D002927:Cimetidine; D006632:Histamine; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D008156:Luciferases; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D004837:Epinephrine