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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Signal transducer and activator of transcription 3alpha and specificity protein 1 interact to upregulate intercellular adhesion molecule-1 in ischemic-reperfused myocardium and vascular endothelium.

OBJECTIVE: Intercellular adhesion molecule-1 ( ICAM-1) is upregulated rapidly on endothelial cells during ischemia-reperfusion (I-R) and mediates tissue leukocyte accumulation. The ICAM-1 proximal promoter contains a signal transducer and activator of transcription ( Stat) binding motif (gamma-interferon activation site [GAS] sequence), which flanks a specificity protein 1 (Sp1) binding site. We examined the roles of Stat and Sp1 in the regulation of ICAM-1 after myocardial I-R. METHODS AND RESULTS: Open-chest anesthetized rats underwent coronary artery occlusion for 35 minutes and reperfusion for 0 to 240 minutes. Stat became activated within 15 minutes after reperfusion, primarily in vascular endothelial cells; the activated Stat protein was identified as Stat3 (alpha-isoform). After phosphorylation on serine 727 (p-S727), Stat3alpha was found in association with the transcriptional regulator Sp1, and the complex bound to an ICAM-1-GAS probe. ICAM-1 expression increased after I-R and lagged shortly behind Stat3alpha activation. In cultured human umbilical vein endothelial (HUVE) cells, activation of Stat3alpha after hypoxia-reoxygenation (H-R) was dependent on the small GTPase Rac1. Transfection of a dominant-negative Stat3 (Y705F) adenovirus or a GAS decoy oligonucleotide reduced ICAM-1 mRNA expression after H-R. Using a reporter gene transfected into HUVE cells, mutation of the GAS element in the ICAM-1 promoter resulted in reduced transcriptional activity after H-R. Sp1 coimmunoprecipitated with p-S727 Stat3 during H-R, and Sp1 or Stat3alpha interfering RNA markedly reduced ICAM-1 mRNA expression. CONCLUSIONS: The Sp1-Stat3 complex appears to play an important role in the upregulation of ICAM-1 transcription after reoxygenation or reperfusion.[1]

References

  1. Signal transducer and activator of transcription 3alpha and specificity protein 1 interact to upregulate intercellular adhesion molecule-1 in ischemic-reperfused myocardium and vascular endothelium. Yang, X.P., Irani, K., Mattagajasingh, S., Dipaula, A., Khanday, F., Ozaki, M., Fox-Talbot, K., Baldwin, W.M., Becker, L.C. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
 
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