scholarly journals Repression of platelet-derived growth factor beta-receptor expression by mitogenic growth factors and transforming oncogenes in murine 3T3 fibroblasts.

1995 ◽  
Vol 15 (3) ◽  
pp. 1244-1253 ◽  
Author(s):  
C Vaziri ◽  
D V Faller
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Cell Surface ◽  
Growth Arrest ◽  
Serum Deprivation ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Mrna Levels ◽  
Beta Receptor ◽  
3T3 Fibroblasts

Platelet-derived growth factor BB (PDGF-BB) is an important extracellular factor for regulating the G0-S phase transition of murine BALB/c-3T3 fibroblasts. We have investigated the expression of the PDGF beta receptor (PDGF beta R) in these cells. We show that the state of growth arrest in G0, resulting from serum deprivation, is associated with increased expression of the PDGF beta R. When the growth-arrested fibroblasts are stimulated to reenter the cell cycle by the mitogenic action of serum or certain specific combinations of growth factors, PDGF beta R mRNA levels and cell surface PDGF-BB-binding sites are markedly downregualted. Oncogene-transformed 3T3 cell lines, which fail to undergo growth arrest following prolonged serum deprivation, express constitutively low levels of the PDGF beta R mRNA and possess greatly reduced numbers of cell surface PDGF receptors, as determined by PDGF-BB binding and Western blotting (immunoblotting). Nuclear runoff assays indicate the mechanism of repression of PDGF beta R expression to be, at least in large part, transcriptional. These data indicate that expression of the PDGF beta R is regulated in a growth state-dependent manner in fibroblasts and suggest that this may provide a means by which cells can modulate their responsiveness to the actions of PDGF.

Control of stable lamellipodia formation by expression of cell surface beta 1,4-galactosyltransferase cytoplasmic domains

1994 ◽  
Vol 107 (9) ◽  
pp. 2535-2545 ◽  
Author(s):  
P.A. Appeddu ◽  
B.D. Shur
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Binding Sites ◽  
Mesenchymal Cell ◽  
Fiber Formation ◽  
Platelet Derived Growth Factor ◽  
Specific Stimulus ◽  
3T3 Fibroblasts ◽  
A Cell ◽  
Lamellipodia Formation

Mesenchymal cell migration on basal lamina is mediated, in part, by the binding of cell surface beta 1,4-galactosyltransferase (GalTase) to specific N-linked oligosaccharides in the E8 domain of laminin. On migrating cells, surface GalTase is anchored to the cytoskeleton; when GalTase is prevented from associating with the cytoskeleton, lamellipodia formation and subsequent migration are inhibited. To define better the involvement of GalTase-cytoskeleton interactions in cell motility, we examined the lamellipodia formation, polarity and migratory behavior of stably transfected 3T3 fibroblasts expressing increased or decreased levels of GalTase capable of interacting with the cytoskeleton. Initially, the motile behavior of individual cells was quantified in the absence of exogenous stimuli. Cells that overexpress GalTase binding sites for the cytoskeleton changed their polarity more frequently and translocated more erratically than did control cells when assayed on laminin substrata. These differences were not observed, however, when cells were plated on fibronectin, which does not contain binding sites for surface GalTase. GalTase-transfected cells were also assayed for their ability to polarize in response to a specific stimulus. In this case, the ability of a cell to reorient towards a gradient of platelet-derived growth factor was found to be directly proportional to the amount of GalTase associated with the cytoskeleton. Differences in response to platelet-derived growth factor were not due to differences in growth factor binding. Indirect immunofluorescence showed that altering the level of GalTase did not affect the ventrally distributed pool of GalTase stably associated with the cytoskeleton; however, stress fiber formation was inhibited. Thus, increasing surface GalTase binding sites for the cytoskeleton leads to erratic, multipolar behavior in the absence of any vectorial stimulus, but the ability to form a functional lamellipodium in response to a stimulus is dependent upon the amount of surface GalTase associated with the cytoskeleton. Apparently, cells are able to regulate cytoskeletal assembly and lamellipodial stability by altering the expression and/or affinity of appropriate matrix receptors, such as GalTase, and their corresponding binding sites in the cytoskeleton.

scholarly journals Platelet-derived growth factor (PDGF)-AB-mediated phosphorylation of PDGF β receptors

1994 ◽  
Vol 297 (2) ◽  
pp. 379-384 ◽  
Author(s):  
S R Coats ◽  
H D Love ◽  
W J Pledger
Keyword(s):  
Growth Factor ◽  
Platelet Derived Growth Factor ◽  
Receptor Dimerization ◽  
Beta Receptor ◽  
3T3 Fibroblasts ◽  
Beta Receptors ◽  
Alpha Receptors ◽  
Alpha Beta ◽  
Subsequent Activation ◽  
Receptor Dimers

Platelet-derived growth factor (PDGF) stimulates the proliferation of Balb/c-3T3 fibroblasts through binding and subsequent activation of PDGF receptors. Activation of the PDGF receptors has been proposed to involve receptor dimerization. PDGF-AB has been shown to bind PDGF alpha and beta receptor subunits to form PDGF alpha beta and alpha alpha receptor dimers. In this paper we demonstrate that, following the down-regulation of PDGF alpha receptors, the binding of PDGF-AB to beta receptors occurred at 37 degrees C but not at 4 degrees C. PDGF-AB stimulated the phosphorylation of PDGF beta receptor monomers in cells depleted of PDGF alpha receptors by prior exposure to PDGF-AA.

scholarly journals Differential modulation of degradative and repair responses of interleukin-1-treated chondrocytes by platelet-derived growth factor

1993 ◽  
Vol 292 (1) ◽  
pp. 129-136 ◽  
Author(s):  
A K Harvey ◽  
S T Stack ◽  
S Chandrasekhar
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Articular Chondrocytes ◽  
Interleukin 1 ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Proteinase Activity ◽  
Proteoglycan Synthesis ◽  
Mrna Levels ◽  
The Matrix

Interleukin 1 (IL-1) plays a dual role in cartilage matrix degeneration by promoting extracellular proteinase action such as the matrix metalloproteinases (increased degradation) and by suppressing the synthesis of extracellular matrix molecules (inhibition of repair). Platelet-derived growth factor (PDGF) is a wound-healing hormone which is released along with IL-1 during the inflammatory response. Since previous studies have shown that PDGF enhances IL-1 alpha effects on metalloproteinase activity, in this report, we have examined whether PDGF modifies IL-1 beta effects on cartilage proteoglycan synthesis. Initially, we confirmed that rabbit articular chondrocytes treated with IL-1 beta + PDGF induced higher proteinase activity, in comparison with IL-1-treated cells. We further observed that the increased proteinase activity correlated with an increase in the synthesis of collagenase/stromelysin proteins and a corresponding increase in the steady-state mRNA levels for both the enzymes. Studies on IL-1 receptor expression suggested that PDGF caused an increase in IL-1 receptor expression which, by augmenting the IL-1 response, may have led to the increase in proteinase induction. Analysis of proteoglycan synthesis confirmed that IL-1 reduced the incorporation of sulphated proteoglycan, aggrecan, into the extracellular matrix of chondrocytes, whereas PDGF stimulated it. However, cells treated with IL-1 + PDGF synthesized normal levels of aggrecan. This is in contrast with cells treated with IL-1 + fibroblast growth factor, in which case only proteinase activity was potentiated. The results allow us to conclude that (a) the two effector functions that play a role in matrix remodelling, namely matrix lysis (proteinase induction) and matrix repair (proteoglycan synthesis), occur via distinct pathways and (b) PDGF may play a crucial role in cartilage repair by initially causing matrix degradation followed by promoting new matrix synthesis.

scholarly journals Down-regulation of cellular platelet-derived growth factor receptors induced by an activated neu receptor tyrosine kinase.

1991 ◽  
Vol 2 (8) ◽  
pp. 651-661 ◽  
Author(s):  
L Lehtola ◽  
M Nistér ◽  
E Hölttä ◽  
B Westermark ◽  
K Alitalo
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Receptor Expression ◽  
Platelet Derived Growth Factor ◽  
Target Cells ◽  
Mrna Levels ◽  
Pdgf Receptor ◽  
Down Regulation ◽  
Beta Receptors ◽  
Neu Oncogene

The functional integration of growth factor signaling occurs at several levels in target cells. One of the most proximal mechanisms is receptor transmodulation, by which one activated receptor can regulate the expression of other receptors in the same cells. Well-established transregulatory loops involve platelet-derived growth factor (PDGF) down-regulation of epidermal growth factor (EGF) receptors and beta-type transforming growth factors modulation of PDGF receptors. We have studied the relationship between neu tyrosine kinase activation and the expression of the PDGF receptors in transfected NIH/3T3 cells. Expression of the neu oncogene, but not of the neu proto-oncogene, was associated with a decrease of PDGF alpha- and beta-receptors on the cell surface, as measured by [125-I]PDGF-AA and -BB binding. These results were corroborated by metabolic labeling and immunoprecipitation of the PDGF beta-receptors. PDGF alpha- and beta-receptor mRNAs were strongly decreased in the neu oncogene-transformed cells in comparison with control cells expressing the neu proto-oncogene. Down-regulation of the PDGF receptors and their mRNAs was also observed after EGF treatment of cells expressing a chimeric EGF receptor/neu receptor, where the neu tyrosine kinase is activated by EGF binding. These results show that the neu tyrosine kinase can down-modulate PDGF receptor expression, and the effect is mediated via decreased PDGF receptor mRNA levels.

scholarly journals Myc Is an Essential Negative Regulator of Platelet-Derived Growth Factor Beta Receptor Expression

2000 ◽  
Vol 20 (18) ◽  
pp. 6768-6778 ◽  
Author(s):  
Sara K. Oster ◽  
Wilson W. Marhin ◽  
Charlotte Asker ◽  
Linda M. Facchini ◽  
Patrick A. Dion ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Cell Types ◽  
Receptor Expression ◽  
Negative Regulator ◽  
Platelet Derived Growth Factor ◽  
Mrna Levels ◽  
Proliferating Cells ◽  
Receptor Complexes ◽  
Β Receptor

ABSTRACT Platelet-derived growth factor BB (PDGF BB) is a potent mitogen for fibroblasts as well as many other cell types. Interaction of PDGF BB with the PDGF β receptor (PDGF-βR) activates numerous signaling pathways and leads to a decrease in receptor expression on the cell surface. PDGF-βR downregulation is effected at two levels, the immediate internalization of ligand-receptor complexes and the reduction in pdgf-βr mRNA expression. Our studies show that pdgf-βr mRNA suppression is regulated by the c-myc proto-oncogene. Both constitutive and inducible ectopic Myc protein can suppress pdgf-βr mRNA and protein. Suppression of pdgf-βr mRNA in response to Myc is specific, since expression of the related receptorpdgf-αr is not affected. We further show that Myc suppresses pdgf-βr mRNA expression by a mechanism which is distinguishable from Myc autosuppression. Analysis of c-Myc-null fibroblasts demonstrates that Myc is required for the repression of pdgf-βr mRNA expression in quiescent fibroblasts following mitogen stimulation. In addition, it is evident that the Myc-mediated repression of pdgf-βr mRNA levels plays an important role in the regulation of basalpdgf-βr expression in proliferating cells. Thus, our studies suggest an essential role for Myc in a negative-feedback loop regulating the expression of the PDGF-βR.

scholarly journals Direct interaction between Shc and the platelet-derived growth factor beta-receptor.

1994 ◽  
Vol 269 (21) ◽  
pp. 15337-15343
Author(s):  
K. Yokote ◽  
S. Mori ◽  
K. Hansen ◽  
J. McGlade ◽  
T. Pawson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Direct Interaction ◽  
Platelet Derived Growth Factor ◽  
Beta Receptor ◽  
Growth Factor Beta
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