title: Transcriptional Upregulation of Plasminogen Activator Inhibitor-1 in Rat Primary Astrocytes by a Proteasomal Inhibitor MG132.
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.
authors.affiliation: Departments of Neuroscience, School of Medicine, Konkuk University, Seoul 143-701, Repulic of Korea ; Departments of SMART Institute of Advanced Biomedical Science, Konkuk University, Seoul 143-701, Repulic of Korea.
authors.forename: Kyu Suk
authors.initials: KS
authors.lastname: Cho
authors.forename: Kyoung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jeon
authors.forename: So Hyun
authors.initials: SH
authors.lastname: Joo
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Cheong
authors.forename: Geon Ho
authors.initials: GH
authors.lastname: Bahn
authors.forename: Hahn Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Seol Heui
authors.initials: SH
authors.lastname: Han
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Sung-Il
authors.initials: SI
authors.lastname: Yang
keywords: Lactacystin; MG132; Plasminogen activator inhibitor-1; Tissue plasminogen activator; p38