Biomol Ther.
2013 Mar;21(2):107-113.
Transcriptional Upregulation of Plasminogen Activator Inhibitor-1 in Rat Primary Astrocytes by a Proteasomal Inhibitor MG132
- Affiliations
-
- 1Department of Neuroscience, School of Medicine, Konkuk University, Seoul 143-701, Repulic of Korea. chanyshin@kku.ac.kr
- 2Department of Neurology, School of Medicine, Konkuk University, Seoul 143-701, Repulic of Korea.
- 3Department of Pharmacology, School of Medicine, Konkuk University, Seoul 143-701, Repulic of Korea. sungilyang@kku.ac.kr
- 4SMART Institute of Advanced Biomedical Science, Konkuk University, Seoul 143-701, Repulic of Korea.
- 5Department of Pharmacy, Sahmyook University, Seoul 139-741, Repulic of Korea.
- 6Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul 130-701, Repulic of Korea.
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.
MeSH Terms
-
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*
Plasminogen
Plasminogen Activator Inhibitor 1
Plasminogen Activators
Plastics
Proteasome Endopeptidase Complex
Proteasome Inhibitors
RNA, Messenger
Serine Proteases
Tissue Plasminogen Activator
Ubiquitin
p38 Mitogen-Activated Protein Kinases
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