Cyclic AMP inhibits agonist-induced heparin-binding EGF gene expression independently of effects on p42/p44 MAPK activation.
Heparin-binding EGF-like growth factor (HB-EGF) mRNA levels are increased up to 20-fold in RIE-1 cells by two agonists that act through distinct receptor types. We demonstrated a common requirement for p42/p44 mitogen-activated protein kinase (MAPK) in this response using the selective MAPK kinase (MEK) inhibitor, PD 098059. Agonist-mediated induction of HB-EGF mRNA was markedly suppressed in cells that had been treated with cyclic AMP-elevating agents. In contrast, the activation of p42 MAPK in response to agonists was not affected by raising cellular cyclic AMP levels. We conclude that cyclic AMP negatively regulates the HB-EGF gene, but that the inhibitory action is either independent of the p42/p44 MAPK pathway or the site of action is distal to MAPK activation.
Ellis
P D
PD
Babraham Institute, Babraham, Cambridge, CB2 4AT, United Kingdom.
Hadfield
K M
KM
Pascall
J C
JC
Brown
K D
KD
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats
C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015056:1-Methyl-3-isobutylxanthine