TGFbeta1 induces a cell-cycle-dependent increase in motility of epithelial cells

1999 ◽  
Vol 112 (4) ◽  
pp. 447-454 ◽  
Author(s):  
D. Zicha ◽  
E. Genot ◽  
G.A. Dunn ◽  
I.M. Kramer
Keyword(s):  
Cell Cycle ◽  
Mass Distribution ◽  
Transforming Growth Factor Beta ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Interference Microscopy ◽  
Response To Treatment ◽  
Gradual Onset ◽  
The Difference ◽  
Cycle Dependent

We have previously shown that addition of type 1 transforming growth factor-beta (TGFbeta1) to an exponentially growing population of mink lung CCl64 cells increases their average intermitotic time from 14.4 to 20.3 hours, predominantly by extending G1 from 7.5 to 13.5 hours. Here we have used the DRIMAPS system (digitally recorded interference microscopy with automatic phase-shifting) for obtaining data on cellular mass distribution, cell motility and morphology. We found no significant change in the cells' rate of mass increase following TGFbeta1 treatment, which implies that the treated cells attained a higher mass during their extended cell cycle and this was confirmed by direct measurement of cell size. However, the cells showed a dramatic motile response to treatment: TGFbeta1-treated cells had a significantly higher time-averaged speed of 36.2 microm hour-1 compared to 14.5 microm hour-1 for the control cells. The time course of the response was gradual, reaching a maximum mean speed of 52.6 microm hour-1 after 15 hours exposure. We found that the gradual onset of the response was probably not due to a slow accumulation of a secondary factor but because cells were dividing throughout the experiment and most of the response to TGFbeta1 occurred only after the first cell division in its presence. Thus, taking only those cells that had not yet divided, the time-averaged speed of treated cells (26.1 micrometer hour-1) was only moderately higher than that of untreated cells (14.9 micrometer hour-1) whereas, for those cells that had divided, the difference in speed between treated cells (45.1 micrometer hour-1) and untreated cells (14.1 microm hour-1) was much greater. Increased speed was a consequence of enhanced protrusion and retraction of the cell margin coupled with an increase in cell polarity. TGFbeta1 also increased the mean spreading of the cells, measured as area-to-mass ratio, from 3.2 to 4.4 micrometer2 pg-1, and the intracellular mass distribution became more asymmetric. The observations indicate that a G2 signal may be necessary to reach maximal motility in the presence of TGFbeta1.

Initiation of growth inhibition by TGF beta 1 is unlikely to occur in G1

1994 ◽  
Vol 107 (12) ◽  
pp. 3469-3475 ◽  
Author(s):  
I.M. Kramer ◽  
R. Patel ◽  
D. Spargo ◽  
P. Riley
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Flow Cytometric Analysis ◽  
Time Lapse ◽  
Target Cells ◽  
Surface Receptors ◽  
Growth Factor Beta ◽  
The Difference

Type beta transforming growth factors represent a family of polypeptides that modulate growth and differentiation. They exert their effect on target cells through interaction with multiple cell surface receptors. Transforming growth factor-beta 1 has a strong inhibitory action on cell division in mink lung CC164 cells, a process that is initiated by immediate induction of junB and phosphorylation of nuclear protein followed by a reduced expression of cdk4. However, its signal transduction pathways are still unresolved. In this study we report a detailed analysis of cell kinetic events following addition of transforming growth factor-beta 1 to mink lung CCL64 cells. We show that transforming growth factor-beta 1 reduces [3H]thymidine incorporation after a delay of 8 hours, which reaches its nadir at 16 hours. The reduced growth rate is maintained for at least 48 hours as shown by flow cytometric analysis of DNA content. Using time-lapse video microscopy it was shown that control cells double on average every 14.4 hours, whereas the transforming growth factor-beta 1-treated cells have a doubling time of on average 20.3 hours. The difference in intermitotic time is a consequence of a prolonged G1 phase (a shift from 7.5 to 13.5 hours on average). However, changes in intermitotic times occur only after cells have undergone division in the presence of transforming growth factor-beta 1 and treated cells finish the ongoing cell cycle exactly like control cells. From these findings we conclude that transforming growth factor-beta 1 may change cell cycle parameters by interfering with cellular events prior to G1.(ABSTRACT TRUNCATED AT 250 WORDS)

Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function

1991 ◽  
Vol 11 (10) ◽  
pp. 4952-4958
Author(s):  
A Zentella ◽  
F M Weis ◽  
D A Ralph ◽  
M Laiho ◽  
J Massagué
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Early Gene ◽  
Tgf Beta ◽  
Suppressive Function ◽  
Growth Factor Beta ◽  
Pai 1

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.

scholarly journals Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells.

1988 ◽  
Vol 107 (2) ◽  
pp. 771-780 ◽  
Author(s):  
G K Owens ◽  
A A Geisterfer ◽  
Y W Yang ◽  
A Komoriya
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Muscle Cells ◽  
Tgf Beta ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Cellular Hypertrophy

We have explored the hypothesis that hypertrophy of vascular smooth muscle cells may be regulated, in part, by growth inhibitory factors that alter the pattern of the growth response to serum mitogens by characterizing the effects of the potent growth inhibitor, transforming growth factor-beta (TGF-beta), on both hyperplastic and hypertrophic growth of cultured rat aortic smooth muscle cells. TGF-beta inhibited serum-induced proliferation of rat aortic smooth muscle cells (ED50 = 2 pM); this is consistent with previously reported observations in bovine aortic smooth muscle cells (Assoian et al. 1982. J. Biol. Chem. 258:7155-7160). Growth inhibition was due in part to a greater than twofold increase in the cell cycle transit time in cells that continued to proliferate in the presence of TGF-beta. TGF-beta concurrently induced cellular hypertrophy as assessed by flow cytometric analysis of cellular protein content (47% increase) and forward angle light scatter (32-50% increase), an index of cell size. In addition to being time and concentration dependent, this hypertrophy was reversible. Simultaneous flow cytometric evaluation of forward angle light scatter and cellular DNA content demonstrated that TGF-beta-induced hypertrophy was not dependent on withdrawal of cells from the cell cycle nor was it dependent on growth arrest of cells at a particular point in the cell cycle in that both cycling cells in the G2 phase of the cell cycle and those in G1 were hypertrophied with respect to the corresponding cells in vehicle-treated controls. Chronic treatment with TGF-beta (100 pM, 9 d) was associated with accumulation of cells in the G2 phase of the cell cycle in the virtual absence of cells in S phase, whereas subsequent removal of TGF-beta from these cultures was associated with the appearance of a significant fraction of cycling cells with greater than 4c DNA content, consistent with development of tetraploidy. Results of these studies support a role for TGF-beta in the control of smooth muscle cell growth and suggest that at least one mechanism whereby hypertrophy and hyperploidy may occur in this, as well as other cell types, is by alterations in the response to serum mitogens by potent growth inhibitors such as TGF-beta.

scholarly journals Early gene responses to transforming growth factor-beta in cells lacking growth-suppressive RB function.

1991 ◽  
Vol 11 (10) ◽  
pp. 4952-4958 ◽  
Author(s):  
A Zentella ◽  
F M Weis ◽  
D A Ralph ◽  
M Laiho ◽  
J Massagué
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Lung Epithelial Cells ◽  
Early Gene ◽  
Tgf Beta ◽  
Suppressive Function ◽  
Growth Factor Beta ◽  
Pai 1

The growth-suppressive function of the retinoblastoma susceptibility gene product, RB, has been implicated in the mediation of growth inhibition and negative regulation of certain proliferation related genes by transforming growth factor-beta 1 (TGF-beta 1). Early gene responses to TGF-beta 1 were examined in order to determine their dependence on the cell cycle and on the growth-suppressive function of RB. TGF-beta 1, which rapidly elevates the steady-state level of junB and PAI-1 mRNAs and decreases that of c-myc mRNA, induces these responses in S-phase populations of Mv1Lu lung epithelial cells containing RB in a phosphorylated state. Since in this state RB is presumed to lack growth-suppressive activity, the response to TGF-beta 1 was also examined in DU145 human prostate carcinoma cells whose mutant RB product lacks growth-suppressive function. In these cells, TGF-beta 1 also decreases c-myc expression at the transcription initiation level. These results suggests that the c-myc, junB, and PAI-1 responses to TGF-beta 1 are not restricted to the G1 phase of the cell cycle and that down-regulation of c-myc expression by TGF-beta 1 can occur through a mechanism independent from the growth-suppressive function of RB.

scholarly journals Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor beta.

1994 ◽  
Vol 179 (5) ◽  
pp. 1495-1506 ◽  
Author(s):  
Y Takahama ◽  
J J Letterio ◽  
H Suzuki ◽  
A G Farr ◽  
A Singer
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Precursor Cells ◽  
Thymic Epithelial Cells ◽  
Tgf Beta ◽  
Developmental Pathway ◽  
Beta Proteins ◽  
Growth Factor Beta

Precursor cells differentiate into mature CD4+ and CD8+ T cells in the inductive environment of the thymus by undergoing a series of distinct developmental steps marked by expression of the coreceptor molecules CD4 and CD8. Among the earliest cells to enter the CD4/CD8 developmental pathway are CD4-CD8lo precursors cells that differentiate into CD4+CD8+ thymocytes. Here we show that differentiation of precursor cells into CD4+CD8+ thymocytes requires at least one cell division and that their progression through a cell cycle is specifically retarded in the thymus by interaction with thymic epithelial cells that express transforming growth factor beta (TGF-beta) proteins. We also demonstrate that TGF-beta proteins, either in solution or bound to cell membranes, can regulate cell cycle progression and differentiation of CD4-CD8lo precursor cells into CD4+CD8+ thymocytes. The regulatory effect of TGF-beta is specific for CD4-CD8lo precursor cells as TGF-beta proteins do not regulate the earlier generation of CD4-CD8lo precursor cells from CD4-CD8- thymocytes. Finally, we demonstrate that TGF-beta proteins are expressed in vivo in the intact thymus on subcapsular and cortical thymic epithelium where they can contact developing CD4-CD8lo precursor cells. Thus, thymic epithelial cells expressing TGF-beta proteins can actively regulate the rate at which CD4+CD8+ thymocytes are generated from CD4-CD8lo precursor cells.

scholarly journals Control of junB and extracellular matrix protein expression by transforming growth factor-beta 1 is independent of simian virus 40 T antigen-sensitive growth-sensitive growth-inhibitory events.

1991 ◽  
Vol 11 (2) ◽  
pp. 972-978 ◽  
Author(s):  
M Laiho ◽  
L Rönnstrand ◽  
J Heino ◽  
J A Decaprio ◽  
J W Ludlow ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Simian Virus 40 ◽  
Plasminogen Activator Inhibitor ◽  
Simian Virus ◽  
T Antigen ◽  
Tgf Beta ◽  
Plasminogen Activator Inhibitor 1

Treatment of Mv1Lu mink lung epithelial cells with transforming growth factor-beta 1 (TGF-beta 1) prevents phosphorylation of the retinoblastoma susceptibility gene product, RB, in late G1 phase of the cell cycle, which is thought to retain RB in a growth-suppressive state. This effect is paralleled by cell cycle arrest in late G1 (M. Laiho, J. A. DeCapric, J. W. Ludlow, D. M. Livingston, and J. Massagué, Cell 62:175-185, 1990). Arrest can be prevented by expression of simian virus 40 T antigen, which binds to underphosphorylated RB, presumably blocking its growth-suppressive activity. The response of cells to TGF-beta 1, however, is complex and includes changes in the levels of expression of genes encoding nuclear transcription factors and extracellular matrix components. To define the relationships among various components of the TGF-beta 1 response, we have investigated the effect of TGF-beta 1 on cells whose growth-inhibitory response to this factor is prevented by T antigen. TGF-beta 1 addition to exponentially growing Mv1Lu cells increased the levels of junB mRNA and of three extracellular matrix proteins: plasminogen activator inhibitor-1, fibronectin, and thrombospondin. Kinetically, the effects on junB and plasminogen activator inhibitor-1 expression occurred faster (half-maximal at 1 to 2 h) than the effects on fibronectin and thrombospondin expression (half-maximal at 6 to 10 h). These effects either preceded or overlapped, respectively, the withdrawal of Mv1Lu cells from the cell cycle. Expression of a transfected T-antigen gene in Mv1Lu cells, however, did not prevent any of these responses to TGF-beta 1. The results indcate that TGF-B1-stimulated expression of junB and extracellular matrix proteins in Mv1Lu cells can occur independently of the T-antigen-sensitive events that lead to growth arrest.

Alterations in Cardiac Structure and Function in a Murine Model of Chronic Alcohol Consumption

2012 ◽  
Vol 18 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Brittany A. Law ◽  
Scott P. Levick ◽  
Wayne E. Carver
Keyword(s):  
Transforming Growth Factor Beta ◽  
Time Course ◽  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiomyocyte Hypertrophy ◽  
Histological Techniques ◽  
Number Of Factors ◽  
Mrna Analysis ◽  
And Function

AbstractMale, wild-type, FVB strain mice were fed a nutritionally complete liquid diet supplemented with 4% ethanol v/v over a time course of 1, 2, 4, 8, 12, and 14 weeks. Controls were offered an isocaloric liquid equivalent and pair fed with their ethanol counterparts. Changes in cardiac physiology were assessed at respective time points via echocardiography. Additionally, the use of histological techniques, mRNA analysis, apoptosis determination, and immunohistochemistry were employed to determine the functional and structural changes on the heart. Echocardiograph analysis revealed a compensatory phase that occurred early in the time course (1–8 weeks) and decompensation reverting toward heart failure at weeks 12 and 14. Throughout the study, an increase in cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis, TGF-β, and the presence of α-SMA-positive cells were determined. A compensatory period in mice treated with ethanol occurred early followed by a transition to a dilated phenotype over time. A number of factors may be involved in this process including the activation of myofibroblasts and their fibrotic activities that is correlated with the presence of transforming growth factor beta.

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