CREB binding to the hypoxia-inducible factor-1 responsive elements in the plasminogen activator inhibitor-1 promoter mediates the glucagon effect.
Plasminogen activator inhibitor-1 (PAI-1) controls the regulation of the fibrinolytic system in blood by inhibiting both urokinase-type and tissue-type plasminogen activators. Enhanced levels of PAI-1 are related to pathological conditions associated with hypoxia or hyperinsulinemia. In this study, we investigated the regulation of PAI-1 expression by glucagon and the cAMP/PKA/CREB signalling pathway in the liver. Stimulation of the cAMP/PKA/CREB signalling cascade by starvation in vivo or glucagon in vitro induced PAI-1 gene expression in liver. Furthermore, this response was associated with enhanced phosphorylation of CREB. By using EMSAs we found that three promoter elements, the HRE2, E-box 4 and E-box 5, were able to bind CREB but only the HRE2 and E5 appeared to be functionally active. Reporter gene assays confirmed that cAMP induced PAI-1 gene transcription via the same element in both human and rat promoters. Interestingly, although the HRE2 was involved, the glucagon/cAMP pathway had no influence on hypoxia-inducible factor-1 (HIF-1) mRNA and protein levels. Thus, CREB binding to the HIF-1 responsive elements in PAI-1 promoter mediates the glucagon effect in the liver.
Dimova
Elitsa Y
EY
Department Chemistry/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany.
Jakubowska
Malgorzata M
MM
Kietzmann
Thomas
T
D000818:Animals; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005934:Glucagon / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020218:Response Elements; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D051793:Hypoxia-Inducible Factor 1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D005934:Glucagon; D000242:Cyclic AMP