Actin-dependent regulation of connective tissue growth factor

2007 ◽  
Vol 292 (5) ◽  
pp. C1732-C1738 ◽  
Author(s):  
Susanne Muehlich ◽  
Iwona Cicha ◽  
Christoph D. Garlichs ◽  
Bettina Krueger ◽  
Guido Posern ◽  
...  

Expression of connective tissue growth factor (CTGF) in endothelial cells is modulated by shear stress affecting the organization of the cytoskeleton. The molecular connection between alterations of actin and CTGF expression was investigated in human umbilical vein endothelial cells (HUVEC) and a microvascular endothelial cell line. Overexpression of nonpolymerizable monomeric actin R62D interfered with stress fiber formation in HUVEC and concomitantly reduced immunoreactive CTGF. In microvascular endothelial cells, flow-dependent upregulation of CTGF was prevented by this actin mutant. In contrast, overexpression of actin S14C strengthened filamentous actin and increased CTGF expression. These data indicated an inverse relationship between CTGF expression and monomeric actin. Coexpression of the mutant actins and different CTGF promoter constructs revealed an actin-sensitive site between 3 and 4.5 kb of the CTGF promoter. A CArG-like box at −3791 bp was responsible for actin-dependent CTGF induction as shown by mutagenesis. Overexpression of actin S14C activated the nonmutated promoter significantly more strongly than the mutated promoter. Actin polymerization is regulated by the small GTPase RhoA and activation of serum response factor (SRF). Overexpression of constitutively active RhoA or SRF significantly increased CTGF protein synthesis. The 4.5-kb promoter construct, but not the construct with a mutation in the CArG box, was activated by SRF or RhoA, providing evidence for a functional role of this site in CTGF induction. These findings provide novel evidence that monomeric actin is the connecting link between alterations in the cytoskeleton and CTGF gene expression and demonstrate the importance of SRF in regulating CTGF transcription.

2011 ◽  
Vol 108 (37) ◽  
pp. 15242-15247 ◽  
Author(s):  
M. A. Guney ◽  
C. P. Petersen ◽  
A. Boustani ◽  
M. R. Duncan ◽  
U. Gunasekaran ◽  
...  

2001 ◽  
Vol 12 (9) ◽  
pp. 1853-1861 ◽  
Author(s):  
JULIANE HEUSINGER-RIBEIRO ◽  
MICHAEL EBERLEIN ◽  
NADIA ABDEL WAHAB ◽  
MARGARETE GOPPELT-STRUEBE

Abstract. The induction of connective tissue growth factor (CTGF) was investigated in a human renal fibroblast cell line that exhibited many characteristics of primary human renal fibroblasts. Induction of CTGF mRNA was observed after treatment of the cells with transforming growth factor-β (TGF-β) or, even more prominently, lysophosphatidic acid (LPA). LPA induced a rapid transient increase in CTGF mRNA expression, with maximal levels being observed after 1 to 2 h. This increase was accompanied by CTGF protein synthesis. Induction of CTGF was insensitive to pertussis toxin and was not dependent on the activation of p42/44 mitogen-activated protein kinases. Inhibition of the proteins of the Rho family with toxin B from Clostridium difficile abrogated basal and LPA-mediated induction of CTGF. Specific targeting of RhoA with C3 exotoxin or of the Rho kinases with the inhibitor Y-27632 similarly prevented induction of CTGF, implicating RhoA as a signaling module downstream of LPA. Inhibition of RhoA depolymerized the actin cytoskeleton, as did treatment with cytochalasin D. Preincubation of the human renal fibroblasts with cytochalasin D prevented induction of CTGF by LPA, indicating a strong contribution of an intact cytoskeleton. Interference with RhoA signaling similarly inhibited the induction of CTGF by TGF-β. Elevation of intracellular levels of cAMP and thus activation of protein kinase A prevented induction of CTGF expression. The cytoskeletal effects of cAMP, however, were reversed by LPA. These data indicate complex interactions involving LPA-mediated activation of RhoA- and protein kinase A-dependent signaling pathways. The data thus demonstrate the regulatory functions of the small GTPase RhoA and of an intact cytoskeleton in the expression of CTGF after stimulation with LPA or TGF-β. Analogous signal transduction pathways were previously demonstrated in rat mesangial cells, suggesting a more general role for RhoA in the regulation of CTGF expression.


2002 ◽  
Vol 24 (7) ◽  
pp. 677-683 ◽  
Author(s):  
Li-Hua Pan ◽  
Takaaki Beppu ◽  
Akira Kurose ◽  
Kohei Yamauchi ◽  
Atsushi Sugawara ◽  
...  

2009 ◽  
Vol 17 (2) ◽  
pp. 291-303 ◽  
Author(s):  
P Laplante ◽  
I Sirois ◽  
M-A Raymond ◽  
V Kokta ◽  
A Béliveau ◽  
...  

2009 ◽  
Vol 285 (7) ◽  
pp. 4328-4336 ◽  
Author(s):  
Jana Samarin ◽  
Julia Wessel ◽  
Iwona Cicha ◽  
Sven Kroening ◽  
Christina Warnecke ◽  
...  

Sign in / Sign up

Export Citation Format

Share Document