Transcriptional Upregulation of Plasminogen Activator Inhibitor-1 in Rat Primary Astrocytes by a Proteasomal Inhibitor MG132.
- Author:
Kyu Suk CHO
1
;
Kyoung Ja KWON
;
Se Jin JEON
;
So Hyun JOO
;
Ki Chan KIM
;
Jae Hoon CHEONG
;
Geon Ho BAHN
;
Hahn Young KIM
;
Seol Heui HAN
;
Chan Young SHIN
;
Sung Il YANG
Author Information
1. Department of Neuroscience, School of Medicine, Konkuk University, Seoul 143-701, Repulic of Korea. chanyshin@kku.ac.kr
- Publication Type:Original Article
- Keywords:
MG132;
Lactacystin;
p38;
Plasminogen activator inhibitor-1;
Tissue plasminogen activator
- MeSH:
Animals;
Astrocytes*;
Brain;
Cell Survival;
Humans;
Neurons;
p38 Mitogen-Activated Protein Kinases;
Plasminogen Activator Inhibitor 1;
Plasminogen Activators*;
Plasminogen*;
Plastics;
Proteasome Endopeptidase Complex;
Proteasome Inhibitors;
Rats*;
RNA, Messenger;
Serine Proteases;
Tissue Plasminogen Activator;
Ubiquitin;
Up-Regulation*
- From:Biomolecules & Therapeutics
2013;21(2):107-113
- CountryRepublic of Korea
- Language:English
-
Abstract:
Plasminogen activator inhibitor-1 (PAI-1) is a member of serine protease inhibitor family, which regulates the activity of tissue plasminogen activator (tPA). In CNS, tPA/PAI-1 activity is involved in the regulation of a variety of cellular processes such as neuronal development, synaptic plasticity and cell survival. To gain a more insights into the regulatory mechanism modulating tPA/PAI-1 activity in brain, we investigated the effects of proteasome inhibitors on tPA/PAI-1 expression and activity in rat primary astrocytes, the major cell type expressing both tPA and PAI-1. We found that submicromolar concentration of MG132, a cell permeable peptide-aldehyde inhibitor of ubiquitin proteasome pathway selectively upregulates PAI-1 expression. Upregulation of PAI-1 mRNA as well as increased PAI-1 promoter reporter activity suggested that MG132 transcriptionally increased PAI-1 expression. The induction of PAI-1 downregulated tPA activity in rat primary astrocytes. Another proteasome inhibitor lactacystin similarly increased the expression of PAI-1 in rat primary astrocytes. MG132 activated MAPK pathways as well as PI3K/Akt pathways. Inhibitors of these signaling pathways reduced MG132-mediated upregulation of PAI-1 in varying degrees and most prominent effects were observed with SB203580, a p38 MAPK pathway inhibitor. The regulation of tPA/PAI-1 activity by proteasome inhibitor in rat primary astrocytes may underlie the observed CNS effects of MG132 such as neuroprotection.
