Faculty Collaboration Database

Regulation of TGF-beta1/MAPK-mediated PAI-1 gene expression by the actin cytoskeleton in human mesangial cells. Exp Cell Res 2007 Apr 01;313(6):1240-50

Date

03/03/2007

Pubmed ID

17328891

Pubmed Central ID

PMC1896147

DOI

10.1016/j.yexcr.2007.01.011

Scopus ID

2-s2.0-33947229059 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

The importance of transforming growth factor-beta1 (TGF-beta1) in plasminogen activator inhibitor-1 (PAI-1) gene expression has been established, but the precise intracellular mechanisms are not fully understood. Our hypothesis is that the actin cytoskeleton is involved in TGF-beta1/MAPK-mediated PAI-1 expression in human mesangial cells. Examination of the distributions of actin filaments (F-actin), alpha-actinin, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunofluorescence and immunoprecipitation revealed that ERK and JNK associate with alpha-actinin along F-actin and that TGF-beta1 stimulation promote the dissociation of ERK and JNK with F-actin. Disassembly of the actin cytoskeleton inhibited phosphorylation of ERK and JNK and modulated PAI-1 expression and promoter activity under both basal and TGF-beta1-stimulated conditions. Stabilizing actin prevented dephosphorylation of ERK and JNK. ERK and JNK inhibitors and overexpressed dominant negative mutants antagonized the ability of TGF-beta1 to increase PAI-1 expression and promoter activity. Disassembly of F-actin also inhibited AP-1 DNA binding activity as determined by electrophoretic mobility shift assay using AP-1 consensus oligonucleotides derived from human PAI-1 promoter. F-actin stabilization prevented loss of AP-1 DNA binding activity. Therefore, changes in actin cytoskeleton modulate the ability of TGF-beta1 to stimulate PAI-1 expression through a mechanism dependent on the activation of MAPK/AP-1 pathways.

Author List

Yang C, Patel K, Harding P, Sorokin A, Glass WF 2nd

Author

Andrey Sorokin PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actins
Cell Line
Cytoskeleton
Enzyme Activation
Gene Expression Regulation
Humans
Mesangial Cells
Mitogen-Activated Protein Kinases
Models, Biological
Plasminogen Activator Inhibitor 1
Signal Transduction
Smad Proteins
Transforming Growth Factor beta1