The human histamine H(2) receptor regulates c-jun and c-fos in a differential manner.
Previously, we demonstrated that activation of the human H(2) receptor (hH(2)R) leads to an increase in c-fos transcription and cell proliferation. The purpose of these studies was to examine whether hH(2)R regulates c-jun expression and, if so, explore the mechanisms by which it does so. Histamine induced an increase in c-jun mRNA in human embryonic kidney cells stably transfected with the hH(2)R (maximal effect: 554.6 +/- 86.8% of control). The protein kinase C (PKC) inhibitors staurosporine (10(-6) M) and GF-109203X (10(-6) M) significantly inhibited histamine-stimulated c-fos mRNA while not altering c-jun expression. The protein kinase A (PKA) pathway inhibitors Rp-cAMP and protein kinase inhibitor did not affect the action of histamine on c-jun or c-fos mRNA. Histamine (10(-4) M) stimulated extracellularly regulated kinase 2 tyrosine phosphorylation. The specific inhibitor of the mitogen-activated protein (MAP) kinase pathway, PD-98059 (5 x 10(-5) M), significantly inhibited histamine-induced c-fos and c-jun mRNA. Of interest, the p70 S6 kinase inhibitor rapamycin (10(-6) M) but not wortmannin decreased histamine-stimulated c-jun mRNA by 58.5 +/- 12% (mean +/- SE, n = 4) while not significantly altering c-fos message. Histamine (10(-4) M) also led to an approximately 4.5-fold increase in Jun NH(2)-terminal kinase activity in a PKC-, PKA-, and MAP kinase-independent but rapamycin-sensitive manner. Our findings suggest that histamine stimulates both c-fos and c-jun mRNA in a differential manner. PKC is involved in histamine-mediated c-fos activation, whereas p70 S6 kinase is important for linkage of this receptor to c-jun.
Wang
L D
LD
Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor 48109, USA.
Wang
M
M
Todisco
A
A
Grand
E
E
del Valle
J
J
D000730:Androstadienes / Q000494:pharmacology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D016758:Genes, jun; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008301:Maleimides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D000077191:Wortmannin
D000730:Androstadienes; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011970:Receptors, Histamine H2; D011994:Recombinant Proteins; D006632:Histamine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019311:Staurosporine; C070515:bisindolylmaleimide I; D020123:Sirolimus; D000077191:Wortmannin