CREB binding to the hypoxia-inducible factor-1 responsive elements in the plasminogen activator inhibitor-1 promoter mediates the glucagon effect

Elitsa Y. Dimova; Malgorzata M. Jakubowska; Thomas Kietzmann

doi:10.1160/TH07-02-0140

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(02): 296-303
DOI: 10.1160/TH07-02-0140

Theme Issue Article

Schattauer GmbH

CREB binding to the hypoxia-inducible factor-1 responsive elements in the plasminogen activator inhibitor-1 promoter mediates the glucagon effect

Elitsa Y. Dimova

¹Department Chemistry/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany

,

Malgorzata M. Jakubowska

¹Department Chemistry/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany

,

Thomas Kietzmann

¹Department Chemistry/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany

› Author Affiliations

Abstract

Summary

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.

Keywords

PAI-1 - glucagon - cAMP - CREB - HIF-1

Full Text

References

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