Uptake and intracellular transport of the connective tissue growth factor: a potential mode of action

2001 ◽  
Vol 359 (1) ◽  
pp. 89-97 ◽  
Author(s):  
Nadia Abdel WAHAB ◽  
Heike BRINKMAN ◽  
Roger M. MASON
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Transport Pathway ◽  
Potential Mode ◽  
Fibrotic Disorders

Connective tissue growth factor (CTGF) is a secreted cysteine-rich protein now considered as an important effector molecule in both physiological and pathological processes. An increasing amount of evidence indicates that CTGF plays a key role in the pathogenesis of different fibrotic disorders including diabetic nephropathy. However, the molecular mechanisms by which CTGF exerts its effects are not known. Here we provide the first evidence for the existence of an intracellular transport pathway for the growth factor in human mesangial cells. Our results demonstrate that CTGF is internalized from the cell surface in endosomes and accumulates in a juxtanuclear organelle from which the growth factor is then translocated into the cytosol. In the cytosol CTGF is phosphorylated by protein kinase C and PMA treatment can enhance this phosphorylation. Phosphorylated CTGF may have an important role in the cytosol, but it is also translocated into the nucleus where it may directly affect transcription.

scholarly journals Decorin Interacts with Connective Tissue Growth Factor (CTGF)/CCN2 by LRR12 Inhibiting Its Biological Activity

2011 ◽  
Vol 286 (27) ◽  
pp. 24242-24252 ◽  
Author(s):  
Cecilia Vial ◽  
Jaime Gutiérrez ◽  
Cristian Santander ◽  
Daniel Cabrera ◽  
Enrique Brandan
Keyword(s):  
Biological Activity ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Core Protein ◽  
Tissue Growth ◽  
Collagen Iii ◽  
Fibrotic Disorders ◽  
Leucine Rich Repeats

Fibrotic disorders are the end point of many chronic diseases in different tissues, where an accumulation of the extracellular matrix occurs, mainly because of the action of the connective tissue growth factor (CTGF/CCN2). Little is known about how this growth factor activity is regulated. We found that decorin null myoblasts are more sensitive to CTGF than wild type myoblasts, as evaluated by the accumulation of fibronectin or collagen III. Decorin added exogenously negatively regulated CTGF pro-fibrotic activity and the induction of actin stress fibers. Using co-immunoprecipitation and in vitro interaction assays, decorin and CTGF were shown to interact in a saturable manner with a Kd of 4.4 nm. This interaction requires the core protein of decorin. Experiments using the deletion mutant decorin indicated that the leucine-rich repeats (LRR) 10–12 are important for the interaction with CTGF and the negative regulation of the cytokine activity, moreover, a peptide derived from the LRR12 was able to inhibit CTGF-decorin complex formation and CTGF activity. Finally, we showed that CTGF specifically induced the synthesis of decorin, suggesting a mechanism of autoregulation. These results suggest that decorin interacts with CTGF and regulates its biological activity.

scholarly journals Low-Density Lipoprotein Induced Expression of Connective Tissue Growth Factor via Transactivation of Sphingosine 1-Phosphate Receptors in Mesangial Cells

2012 ◽  
Vol 26 (5) ◽  
pp. 833-845 ◽  
Author(s):  
Hesham M. El-Shewy ◽  
Mimi Sohn ◽  
Parker Wilson ◽  
Mi Hye Lee ◽  
Samar M. Hammad ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Pertussis Toxin ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Low Density ◽  
Induced Expression ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Abstract The pro-fibrotic connective tissue growth factor (CTGF) has been linked to the development and progression of diabetic vascular and renal disease. We recently reported that low-density lipoproteins (LDL) induced expression of CTGF in aortic endothelial cells. However, the molecular mechanisms are not fully defined. Here, we have studied the mechanism by which LDL regulates CTGF expression in renal mesangial cells. In these cells, treatment with pertussis toxin abolished LDL-stimulated activation of ERK1/2 and c-Jun N-terminal kinase (JNK), indicating the involvement of heterotrimeric G proteins in LDL signaling. Treatment with LDL promoted activation and translocation of endogenous sphingosine kinase 1 (SK1) from the cytosol to the plasma membrane concomitant with production of sphingosine-1-phosphate (S1P). Pretreating cells with SK inhibitor, dimethylsphinogsine or down-regulation of SK1 and SK2 revealed that LDL-dependent activation of ERK1/2 and JNK is mediated by SK1. Using a green fluorescent protein-tagged S1P1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that LDL induced S1P receptor activation. Pretreating cells with S1P1/S1P3 receptor antagonist VPC23019 significantly inhibited activation of ERK1/2 and JNK by LDL, suggesting that LDL elicits G protein-dependent activation of ERK1/2 and JNK by stimulating SK1-dependent transactivation of S1P receptors. Furthermore, S1P stimulation induced expression of CTGF in a dose-dependent manner that was markedly inhibited by blocking the ERK1/2 and JNK signaling pathways. LDL-induced CTGF expression was pertussis toxin sensitive and inhibited by dimethylsphinogsine down-regulation of SK1 and VPC23019 treatment. Our data suggest that SK1-dependent S1P receptor transactivation is upstream of ERK1/2 and JNK and that all three steps are required for LDL-regulated expression of CTGF in mesangial cells.

Connective Tissue Growth Factor Immunohistochemical Expression Is Associated With Gallbladder Cancer Progression

2013 ◽  
Vol 137 (2) ◽  
pp. 245-250 ◽  
Author(s):  
Patricia Garcia ◽  
Pamela Leal ◽  
Hector Alvarez ◽  
Priscilla Brebi ◽  
Carmen Ili ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Gallbladder Cancer ◽  
Connective Tissue Growth Factor ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Tissue Growth ◽  
Chronic Cholecystitis ◽  
Rank Test ◽  
Immunohistochemical Expression

Context.— Gallbladder cancer (GBC) is an aggressive neoplasia associated with late diagnosis, unsatisfactory treatment, and poor prognosis. Molecular mechanisms involved in GBC pathogenesis remain poorly understood. Connective tissue growth factor (CTGF) is thought to play a role in the pathologic processes and is overexpressed in several human cancers, including GBC. No information is available about CTGF expression in early stages of gallbladder carcinogenesis. Objective.— To evaluate the expression level of CTGF in benign and malignant lesions of gallbladder and its correlation with clinicopathologic features and GBC prognosis. Design.— Connective tissue growth factor protein was examined by immunohistochemistry on tissue microarrays containing tissue samples of chronic cholecystitis (n = 51), dysplasia (n = 15), and GBC (n = 169). The samples were scored according to intensity of staining as low/absent and high CTGF expressers. Statistical analysis was performed using the χ2 test or Fisher exact probability test with a significance level of P < .05. Survival analysis was assessed by the Kaplan-Meier method and the log-rank test. Results.— Connective tissue growth factor expression showed a progressive increase from chronic cholecystitis to dysplasia and then to early and advanced carcinoma. Immunohistochemical expression (score ≥2) was significantly higher in advanced tumors, in comparison with chronic cholecystitis (P < .001) and dysplasia (P = .03). High levels of CTGF expression correlated with better survival (P = .04). Conclusions.— Our results suggest a role for CTGF in GBC progression and a positive association with better prognosis. In addition, they underscore the importance of considering the involvement of inflammation on GBC development.

Connective tissue growth factor antagonizes transforming growth factor-β1/Smad signalling in renal mesangial cells

2011 ◽  
Vol 441 (1) ◽  
pp. 499-510 ◽  
Author(s):  
Helen C. O'Donovan ◽  
Fionnuala Hickey ◽  
Derek P. Brazil ◽  
David H. Kavanagh ◽  
Noelynn Oliver ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Transcriptional Responses ◽  
Cell Contractility ◽  
Tgf Β1

The critical involvement of TGF-β1 (transforming growth factor-β1) in DN (diabetic nephropathy) is well established. However, the role of CTGF (connective tissue growth factor) in regulating the complex interplay of TGF-β1 signalling networks is poorly understood. The purpose of the present study was to investigate co-operative signalling between CTGF and TGF-β1 and its physiological significance. CTGF was determined to bind directly to the TβRIII (TGF-β type III receptor) and antagonize TGF-β1-induced Smad phosphorylation and transcriptional responses via its N-terminal half. Furthermore, TGF-β1 binding to its receptor was inhibited by CTGF. A consequent shift towards non-canonical TGF-β1 signalling and expression of a unique profile of differentially regulated genes was observed in CTGF/TGF-β1-treated mesangial cells. Decreased levels of Smad2/3 phosphorylation were evident in STZ (streptozotocin)-induced diabetic mice, concomitant with increased levels of CTGF. Knockdown of TβRIII restored TGF-β1-mediated Smad signalling and cell contractility, suggesting that TβRIII is key for CTGF-mediated regulation of TGF-β1. Comparison of gene expression profiles from CTGF/TGF-β1-treated mesangial cells and human renal biopsy material with histological diagnosis of DN revealed significant correlation among gene clusters. In summary, mesangial cell responses to TGF-β1 are regulated by cross-talk with CTGF, emphasizing the potential utility of targeting CTGF in DN.

INTERLEUKIN-1BETA INHIBITS CONNECTIVE TISSUE GROWTH FACTOR AND FIBRONECTIN PRODUCTION CAUSED BY ANGIOTENSIN II IN MESANGIAL CELLS

2004 ◽  
Vol 22 (Suppl. 2) ◽  
pp. S42-S43
Author(s):  
E. Sánchez-López ◽  
M. Ruperez ◽  
J. Rodriguez-Vita ◽  
V. Esteban ◽  
A. López ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth ◽  
Interleukin 1Beta

scholarly journals Nitric oxide down-regulates connective tissue growth factor in rat mesangial cells

2002 ◽  
Vol 62 (2) ◽  
pp. 401-411 ◽  
Author(s):  
Annette Keil ◽  
Ingrid E. Blom ◽  
Roel Goldschmeding ◽  
Harald D. Rupprecht
Keyword(s):  
Nitric Oxide ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Mesangial Cells ◽  
Tissue Growth
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