Activation of Protein Kinase C Inhibits the Expression of Connective Tissue Growth Factor

doi:10.1006/bbrc.2000.3314

Biochemical and Biophysical Research Communications

Volume 275, Issue 2, 28 August 2000, Pages 312-321

https://doi.org/10.1006/bbrc.2000.3314 Get rights and content

Abstract

Connective tissue growth factor (CTGF) is a member of a protein family in which 38 cysteine residues are conserved. Although a wide variety of important biological functions have been ascribed to these proteins in recent years, the regulation of their gene expression for most members is virtually unknown. We studied the effects of protein kinase C (PKC) and tyrosine kinase on the expression of CTGF and observed that at the mRNA level CTGF expression is inhibited by the activation of PKC, but stimulated by the inhibition of PKC and tyrosine kinase. We further determined that the novel and the classical PKC isoforms are needed for the inhibition, but the atypical isoforms are not involved. Our data suggest that phosphorylation on serine/threonine and tyrosine by PKC and by tyrosine kinase are all inhibitory to the expression of CTGF.

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Molecular evolution of connective tissue growth factor in Cyprinidae (Teleostei: Cypriniformes)
2008, Progress in Natural Science
Connective tissue growth factor (CTGF) plays an important role in regulation of cell growth, differentiation, apoptosis and individual development in animals. The study of sequences variation and molecular evolution of CTGF gene across various species of the cyprinid could be helpful for understanding of speciation and gene divergence in this kind of fish. In this study, 19 novel sequences of CTGF gene were obtained from the representative species of the family Cyprinidae using PCR amplification, cloning and sequencing. Phylogenetic relationships of Cyprinidae were reconstructed by neighbor-joining (NJ), maximum parsimony (MP), maximum likelihood (ML) and Bayesian method. Oryzias latipes from the family Cyprinodontidae was assigned to be the outgroup taxon. Leuciscini and Barbini were clustered into the monophyletic lineages, respectively, with the high nodal supports. The estimation of the ratio of non-synonymous to synonymous substitution (dN/dS) for the various branches indicated that there stood the different evolution rates between the Leuciscini and the Barbini. With the ratio of dN/dS of the Leuciscini being lower than that of the Barbini, species within the Barbini were demonstrated to be subjected to the relatively less selection pressure and under the relaxable evolution background. A 6 bp indel (insertion/deletion) was found at the 5′ end of CTGF gene of Cyprinidae, and this 6 bp deletion only appeared in the Leuciscini, which is a typical characteristic of the Leuciscini and provides evidence for the monophylogeny of the Leuciscini. For the amino acid sequences of CTGF protein, the most variations and indels were distributed in the signal region and IGFBP region of this protein, implying that these variations were correlated with the regulation of the CTGF gene expression and protein activity.
Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium
2005, Journal of Biological Chemistry
Citation Excerpt :
Our results have demonstrated that activation of PKC, depending on the isoforms involved, could either increase or suppress CTGF expression in response to AngII. Previously, Fan et al. (25) have shown that CTGF expression is inhibited in fibroblasts by PMA, a potent general PKC activator of conventional and novel PKC isoforms, suggesting that PKC activation might inhibit CTGF expression. However, this observation did not provide information regarding the specific action of individual PKC isoforms in cardiomyocytes.
Protein kinase C (PKC) and angiotensin II (AngII) can regulate cardiac function in pathological conditions such as in diabetes or ischemic heart disease. We have reported that expression of connective tissue growth factor (CTGF) is increased in the myocardium of diabetic mice. Now we showed that the increase in CTGF expression in cardiac tissues of streptozotocin-induced diabetic rats was reversed by captopril and islet cell transplantation. Infusion of AngII in rats increased CTGF mRNA expression by 15-fold, which was completely inhibited by co-infusion with AT1 receptor antagonist, candesartan. Similarly, incubation of cultured cardiomyocytes with AngII increased CTGF mRNA expression by 2-fold, which was blocked by candesartan and a general PKC inhibitor, GF109203X. The role of PKC isoform-dependent action was further studied using adenoviral vector-mediated gene transfer of dominant negative (dn) PKC or wild type PKC isoforms. Expression of dnPKCα, -ϵ, and -ζ isoforms suppressed AngII-induced CTGF expression in cardiomyocytes. In contrast, expression of dominant negative PKCδ significantly increased AngII-induced CTGF expression, whereas expression of wild type PKCδ inhibited this induction. This inhibitory effect was further confirmed in the myocardium of transgenic mice with cardiomyocyte-specific overexpression of PKCδ (δTg mice). Thus, AngII can regulate CTGF expression in cardiomyocytes through a PKC activation-mediated pathway in an isoform-selective manner both in physiological and diabetic states and may contribute to the development of cardiac fibrosis in diabetic cardiomyopathy.
Signaling events required for transforming growth factor-β stimulation of connective tissue growth factor expression by cultured human lung fibroblasts
2001, Archives of Biochemistry and Biophysics
It is possible that many of the fibrogenic effects of transforming growth factor-β (TGF-β) are mediated by connective tissue growth factor (CTGF). In the present work, we show that TGF-β1 produces a 5- to 6-fold increase in CTGF expression by cultured human lung fibroblasts that is due mainly to increased transcription. The half-life of CTGF mRNA is 1.96 h, consistent with its role as a cytokine. In addition to requiring Smad activity, based upon the effects of specific inhibitors, the TGF-β intracellular signaling pathway requires the activity of a phosphatidylcholine-specific phospholipase C, a protein kinase C, and one or more tyrosine kinases. It is also likely that the pathway requires a member of the Ras superfamily of small GTPases, but not trimeric G proteins. Pharmacologic inhibition of TGF-β stimulation of CTGF expression may be an effective therapeutic approach to a variety of undesirable fibrotic reactions.
Static Pressure Regulates Connective Tissue Growth Factor Expression in Human Mesangial Cells
2001, Journal of Biological Chemistry
Citation Excerpt :
In contrast, our results showed that increased CTGF expression and apoptosis in human mesangial cells exposed to high static pressure is protein kinase C-independent, contrary to the effect of high glucose-induced CTGF expression in rat mesangial cells, which is protein kinase C-dependent (26). Interestingly, Fan et al. (27) reported that activation of protein kinase C inhibited CTGF induction. A recent report by Suzumaet al. (7) indicated that vascular endothelial growth factor (VEGF) induced up-regulation of CTGF expression in bovine retinal capillary cells.
Connective tissue growth factor (CTGF) is overexpressed in a variety of fibrotic disorders such as renal fibrosis and atherosclerosis. Fibrosis is a common final pathway of renal diseases of diverse etiology, including inflammation, hemodynamics, and metabolic injury. Mechanical strains such as stretch, shear stress, and static pressure are possible regulatory elements in CTGF expression. In this study, we examined the ability of static pressure to modulate CTGF gene expression in cultured human mesangial cells. Low static pressure (40–80 mm Hg) stimulated cell proliferation via a protein kinase C-dependent pathway. In contrast, high static pressure (100–180 mm Hg) induced apoptosis in human mesangial cells. This effect was reversed by treatment with CTGF antisense oligonucleotide but not with transforming growth factor β1-neutralizing antibody or protein kinase C inhibitor. High static pressure not only up-regulated the expression of CTGF, but also the expression of extracellular matrix proteins (collagen I and IV, laminin). This up-regulation of extracellular matrix proteins was also reversed by treatment with CTGF antisense oligonucleotide. As judged by mRNA expression of a total of 1100 genes, including apoptosis-associated genes using DNA microarray techniques, recombinant CTGF protein induced apoptosis by down-regulation of a number of anti-apoptotic genes. Overexpression of CTGF in mesangial cells by transient transfection had similar effects. Taken together, these results suggest that high blood pressure up-regulates CTGF expression in mesangial cells. High levels of CTGF in turn enhance extracellular matrix production and induce apoptosis in mesangial cells, and may contribute to remodeling of mesangium and ultimately glomerulosclerosis.
AFAP1 is a novel downstream mediator of TGF-β1 for CCN2 induction in osteoblasts
2015, PLoS ONE
The role of CTGF in the diabetic rat retina and its relationship with VEGF and TGF-β<inf>2</inf>, elucidated by treatment with CTGFsiRNA
2010, Acta Ophthalmologica

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^☆: Abbreviations used: CTGF, connective tissue growth factor; TGF-β, transforming growth factor β; PDGF, platelet-derived growth factor; EGF, epidermal growth factor; TNF-α, tumor necrosis factor; IGF-I, insulin-like growth factor; FGF, fibroblast growth factor; PMA, phorbol 12-myristate 13-acetate; DAG, diacylglyceral; SMC, smooth muscle cells.

¹: To whom correspondence should be addressed. Fax: (617) 432-2793. E-mail: [email protected].

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Regular ArticleActivation of Protein Kinase C Inhibits the Expression of Connective Tissue Growth Factor☆

Abstract

J. Invest. Dermatol.

J. Biol. Chem.

Exp. Cell. Res.

Cytokine Growth Factor Rev.

J. Biol. Chem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

J. Biol. Chem.

Cell

Am. J. Pathol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta.

Curr. Opin. Cell Biol.

Trends Biochem. Sci.

Metabolism

J. Invest. Dermatol.

Connective tissue growth factor: A cysteine-rich mitogen secreted by human vascular endothelial cells is related the SRC-induced immediate early gene product CEF-10

J. Cell Biol.

Inhibition of endogenous expression of connective tissue growth factor by its antisense oligonucleotide and antisense RNA suppresses proliferation and migration of vascular endothelial cells

J. Biochem.

Regular Article
Activation of Protein Kinase C Inhibits the Expression of Connective Tissue Growth Factor☆