The human histamine H2 receptor regulates c-jun and c-fos in a differential manner

• Published in: American Journal of Physiology: Cell Physiology 2000-06, Vol.278 (6), p.C1246
• Main Authors: Wang, L. D, Wang, M, Todisco, A, Grand, E, del Valle, J
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.2000.278.6.c1246

Department of Internal Medicine, The University of Michigan Medical Center, Ann Arbor, Michigan 48109 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 × 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 ~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 . signal transduction; mitogen-activated protein kinase