Thymosin beta 4 induces the synthesis of plasminogen activator inhibitor 1 in cultured endothelial cells and increases its extracellular expression.
Thymosin beta 4(T beta 4), a 4.9-kDa polypeptide primarily known as a main G-actin-sequestering peptide, is present in high concentrations in various cells and in the circulation. We have found that T beta 4 upregulates the expression of plasminogen activator inhibitor 1 (PAI-1) in endothelial cells measured both at the level of mRNA and protein synthesis. This effect seems to be cell specific and was not observed when other cells such as human fibroblasts, PC3, and U937 were tested. T beta 4 significantly activated the PAI-1 promoter in EA.hy 926 cells transiently transfected either with plasmid p800LUC containing PAI-1 promoter fragment (-800 to +71) or the PAI-1 promoter linked with green fluorescent protein. T beta 4 mediated up-regulation of PAI-1 involved activation of the mitogen-activated protein kinase cascade. Furthermore, T beta 4 enhanced c-Fos/c-Jun DNA-binding activity to the activator protein 1 (AP-1)-like element (-59 to -52). The specificity of this binding activity was demonstrated by competition electrophoretic mobility shift assay and after transfection of EA.hy 926 cells with the mutated PAI-1 promoter. Taken together, these data indicate that, in response to T beta 4 stimulation, AP-1 activity increases to enhance PAI-1 transcription through its unique AP-1-like element at -59 to -52 in the PAI-1 promoter.
Al-Nedawi
Khalid N I
KN
Center for Medical Biology and Microbiology, Polish Academy of Sciences, Lodz, Poland.
Czyz
Malgorzata
M
Bednarek
Radoslaw
R
Szemraj
Janusz
J
Swiatkowska
Maria
M
Cierniewska-Cieslak
Aleksandra
A
Wyczolkowska
Janina
J
Cierniewski
Czeslaw S
CS
D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D013947:Thymosin / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D000099201:Thymosin beta(4)
D017395:Plasminogen Activator Inhibitor 1; D013947:Thymosin; D018808:Transcription Factor AP-1; D000099201:Thymosin beta(4)