TGF-β induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop

Battegay, Edouard; Raines, Elaine W.; Seifert, Ronald A.; Bowen‐Pope, Daniel F.; Ross, Russell

doi:10.1016/0092-8674(90)90448-n

Cited by 708 publications

(399 citation statements)

References 46 publications

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“…Previously, several groups have shown that TGF-f stimulates the growth of fibroblastic cell types via an autocrine production of PDGF-related peptides (Leof et al, 1986;Soma and Grotendorst, 1989;Battegay et al, 1990). Our studies with human foreskin fibroblasts indicated that TGF-f stimulated the synthesis and secretion of peptides with molecular weights (38 kDa) and biological and immunological activities similar to CTGF.…”

Section: Resultsmentioning

confidence: 55%

“…In AKR-2B cells TGF-fl induces the expression of the PDGF B chain gene (Leof et al, 1986), whereas in fibroblasts the PDGF A chain gene is induced (Paulsson et al, 1987b;Soma and Grotendorst, 1989). The PDGF A chain gene is also induced in vascular smooth muscle cells treated with TGF-f (Battegay et al, 1990;Majack et al, 1990). However, the level of PDGF A chain transcript present in our cells is much lower than the level of CTGF mRNA, and we have not been able to detect Lau and Nathans, 1987).…”

Section: Discussionmentioning

confidence: 99%

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Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.

Igarashi

Okochi

Bradham

et al. 1993

MBoC

663

581

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Connective tissue growth factor (CTGF) is a cysteine-rich peptide that exhibits platelet-derived growth factor (PDGF)-like biological and immunological activities. CTGF is a member of a family of peptides that include serum-induced immediate early gene products, a v-src-induced peptide, and a putative avian transforming gene, nov. In the present study, we demonstrate that human foreskin fibroblasts produce high levels of CTGF mRNA and protein after activation with transforming growth factor beta (TGF-beta) but not other growth factors including PDGF, epidermal growth factor, and basic fibroblast growth factor. Because of the high level selective induction of CTGF by TGF-beta, it appears that CTGF is a major autocrine growth factor produced by TGF-beta-treated human skin fibroblasts. Cycloheximide did not block the large TGF-beta stimulation of CTGF gene expression, indicating that it is directly regulated by TGF-beta. Similar regulatory mechanisms appear to function in vivo during wound repair where there is a coordinate expression of TGF-beta 1 before CTGF in regenerating tissue, suggesting a cascade process for control of tissue regeneration and repair.

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Section: Resultsmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.

Igarashi

Okochi

Bradham

et al. 1993

MBoC

663

581

View full text Add to dashboard Cite

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“…35 Overall, TGF-␤ is recognized as a potent growth inhibitor in cells of epithelial origin 36 -41 and a growth stimulator in fibroblast-type cells. 23,25,42 Although VICs are fibroblast-type cells, the anti-proliferative response in these fibroblasts could be partially explained by the fact that they are derived from surface endothelial cells that have undergone epithelial-to-mesenchymal transformation during embryonic development. 2 It is possible that VICs from adult heart valves still possess characteristics of valve endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…8 Although the beneficial role of TGF-␤ in wound repair has been studied, its effects on cell growth remain controversial, owing to its context-dependent nature. Depending on TGF-␤ concentration, 23,24 cell type of interest, 25 and degree of cell differentiation, 26 varying responses in proliferation and apoptosis have been reported. Because VIC growth in vitro is poorly understood, we investigated the regulation of VIC proliferation by TGF-␤.…”

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confidence: 99%

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Gotlieb

2011

The American Journal of Pathology

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Although valve interstitial cell (VIC) growth is an essential feature of injured and diseased valves, the regulation of VIC growth is poorly understood. Transforming growth factor (TGF)-␤ promotes VIC proliferation in early-stage wound repair; thus, herein, we tested the hypothesis that TGF-␤ regulates VIC proliferation under normal nonwound conditions using low-density porcine VIC monolayers. Cell numbers were counted during a 10-day period, whereas proliferation and apoptosis were quantified by bromodeoxyuridine staining and TUNEL, respectively. The extent of retinoblastoma protein phosphorylation and expression of cyclin D1, CDK 4, and p27 were compared using Western blot analysis. Adhesion was quantified using a trypsin adhesion assay, and morphological change was demonstrated by immunofluorescence localization of ␣-smooth muscle actin and vinculin. TGF-␤-treated VICs were rhomboid; significantly decreased in number, proliferation, and retinoblastoma protein phosphorylation; and concomitantly had decreased expression of cyclin D1/CDK4 and increased expression of p27. TGF-␤-treated VICs adhered better to substratum and had more vinculin plaques and ␣-smooth muscle actin stress fibers than did controls. Thus, the regulation of VIC growth by TGF-␤ is context dependent. TGF-␤ prevents excessive heart valve growth under normal physiological conditions while it promotes cell proliferation in the early stages of repair, when increased VICs are required.

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“…In at least some cases, the growth-inhibitory effect of TGF-, is caused by a decrease in transcription of the c-myc gene (36), which is probably mediated by inhibition of phosphorylation of the retinoblastoma susceptibility gene product, pRB (20,21,31,37). In contrast, the growth-stimulatory effect on some connective tissue cells appears to be mediated by the stimulation of an autocrine mechanism involving plateletderived growth factor secretion (2,25).…”

Section: Plasmidsmentioning

confidence: 99%

Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene.

Riccio¹,

Pedone²,

Lund³

et al. 1992

Mol. Cell. Biol.

103

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Transforming growth factor 13 (TGF-3) is the name of a group of closely related polypeptides characterized by a multiplicity of effects, including regulation of extracellular proteolysis and turnover of the extracellular matrix. Its cellular mechanism of action is largely unknown. TGF-131 is a strong and fast inducer of type 1 plasminogen activator inhibitor gene transcription. We have identified a TGF-131-responsive element in the 5'-flanking region of the human type 1 plasminogen activator inhibitor gene and shown that it is functional both in its natural context and when fused to a heterologous nonresponsive promoter. Footprinting and gel retardation experiments showed that two different nuclear factors, present in extracts from both TGF-131-treated and nontreated cells, bind to adjacent sequences contained in the responsive unit. A palindromic sequence binds a trans-acting factor(s) of the CCAAT-binding transcription factor-nuclear factor I family. A partially overlapping dyad symmetry interacts with a second protein that much evidence indicates to be USF. USF is a transactivator belonging to the basic helix-loop-helix family of transcription factors. Mutations which abolish the binding of either CCAAT-binding transcription factor-nuclear factor I or USF result in reduction of transcriptional activation upon exposure to TGF-131, thus showing that both elements of the unit are necessary for the TGF-131 response. We discuss the possible relationship of these findings to the complexity of the TGF-13 action.Transforming growth factor I0 (TGF-3) is a general regulator of cellular activities with a multiplicity of effects in the normal organism. TGF-ps include a group of chemically closely related 25,000-Mr dimeric polypeptides, TGF-pl, , with largely identical effects. (Unless otherwise specified, "TGF-P3" will refer to TGF-fi1 heterodimers throughout the rest of the text.) TGF-,B can be synthesized by most cells of the organism and is stored in large quantities in blood platelets. It acts presumably in an autocrine and paracrine manner. Besides affecting cellular proliferation, TGF-3 influences the differentiation of several cell types; for instance, it inhibits myogenesis and adipogenesis and stimulates chondrogenesis. TGF-, regulates the turnover of the extracellular matrix. It stimulates production by fibroblasts of extracellular matrix components, such as type I, II, and III procollagen, fibronectin, and proteoglycans, and of cellular receptors for such proteins. TGF-1 inhibits production of enzymes catalyzing degradation of the extracellular matrix and stimulates production of inhibitors of such enzymes (22,27,31,41,47).It has previously been demonstrated that TGF-p induces type 1 inhibitor of plasminogen activators (PAI-1) in cultured human fibroblasts (24,26). PAI-1 is an important regulator of plasminogen activation and thus of extracellular proteolytic events, including fibrinolysis and degradation of the extracellular matrix (1, 6). The induction of PAI-1 protein by * Corresponding author. TGF-0 was la...

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TGF-β induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop

Cited by 708 publications

References 46 publications

Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.

Regulation of connective tissue growth factor gene expression in human skin fibroblasts and during wound repair.

Transforming Growth Factor-β Regulates the Growth of Valve Interstitial Cells in Vitro

Transforming growth factor beta 1-responsive element: closely associated binding sites for USF and CCAAT-binding transcription factor-nuclear factor I in the type 1 plasminogen activator inhibitor gene.

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