TGF-β1 -Induced Expression of the Anti-Apoptotic PAI-1 Protein Requires EGFR Signaling

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.

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Blocking the Class I Histone Deacetylase Ameliorates Renal Fibrosis and Inhibits Renal Fibroblast Activation via Modulating TGF-Beta and EGFR Signaling

PLoS ONE ◽

10.1371/journal.pone.0054001 ◽

2013 ◽

Vol 8 (1) ◽

pp. e54001 ◽

Cited By ~ 85

Author(s):

Na Liu ◽

Song He ◽

Li Ma ◽

Murugavel Ponnusamy ◽

Jinhua Tang ◽

...

Keyword(s):

Histone Deacetylase ◽

Renal Fibrosis ◽

Class I ◽

Tgf Beta ◽

Egfr Signaling ◽

Fibroblast Activation

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

Molecular and Cellular Biology ◽

10.1128/mcb.11.10.4952 ◽

1991 ◽

Vol 11 (10) ◽

pp. 4952-4958 ◽

Cited By ~ 72

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.

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Effects of TGF-beta and TNF-alpha on procoagulant and fibrinolytic pathways of human tracheal epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.267.6.l693 ◽

1994 ◽

Vol 267 (6) ◽

pp. L693-L703 ◽

Cited By ~ 10

Author(s):

S. Idell ◽

A. Kumar ◽

C. Zwieb ◽

D. Holiday ◽

K. B. Koenig ◽

...

Keyword(s):

Epithelial Cells ◽

Plasminogen Activator ◽

Fibrinolytic Activity ◽

Transforming Growth Factor ◽

Tnf Alpha ◽

Tgf Beta ◽

Tracheal Epithelial Cells ◽

Fibrin Formation ◽

Tracheal Epithelial ◽

Pai 1

The epithelial lining of the airways is subject to injury through several processes, including infections, bronchiolitis, and fume exposures. Because airway fibrin deposition influences the course of local injury, we examined how two inflammatory cytokines influenced fibrin formation and clearance in human tracheal epithelial cells (TEC). TEC were treated with transforming growth factor-beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha). TNF-alpha increased release of tissue factor (TF)-related procoagulant activity that, through generation of factor Xa, promotes assembly of the prothrombinase complex at the cell surface. Fibrinolytic activity was plasminogen dependent and due to both urokinase (uPA) and tissue plasminogen activator (tPA). The cells expressed plasminogen activator inhibitor 1 (PAI-1), but relatively little PAI-2. Depression of fibrinolysis by TGF-beta correlated with increased PAI-1. Conversely, TNF-alpha increased plasminogen activator (PA) activity due to increased uPA. Fibrinolytic activity was inhibited by actinomycin D and cyclohexamide, but changes in mRNAs for uPA, tPA, PAI-1, and TF by either cytokine were not appreciable. PAI-2 mRNA was not found. The data indicate that TGF-beta decreases the fibrinolytic capacity of TEC, suggesting that this cytokine promotes fibrin retention. TNF-alpha increases expression of both procoagulant and fibrinolytic activities; this differential regulation could favor both pericellular fibrin formation and dissolution.

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Transforming growth factor beta 1 prevents cytokine-mediated inhibitory effects and induction of nitric oxide synthase in the RINm5F insulin-containing beta-cell line

Journal of Endocrinology ◽

10.1677/joe.0.1550567 ◽

1997 ◽

Vol 155 (3) ◽

pp. 567-575 ◽

Cited By ~ 12

Author(s):

JG Mabley ◽

JM Cunningham ◽

N John ◽

MA Di Matteo ◽

IC Green

Keyword(s):

Nitric Oxide ◽

Growth Factor ◽

Nitric Oxide Synthase ◽

Transforming Growth Factor ◽

Tgf Beta ◽

Inhibitory Effects ◽

Rinm5f Cells ◽

Induced Expression ◽

Beta Cell Line ◽

Oxide Synthase

The aim of this study was to examine if the growth factor, transforming growth factor beta 1 (TGF beta 1), could prevent induction of nitric oxide synthase and cytokine-mediated inhibitory effects in the insulin-containing, clonal beta cell line RINm5F. Treatment of RINm5F cells for 24 h with interleukin-1 beta (IL-1 beta) (100 pM) induced expression of nitric oxide synthase and inhibited glyceraldehyde-stimulated insulin secretion. Combinations of IL-1 beta (100 pM), tumour necrosis factor-alpha (100 pM) and interferon-gamma (100 pM) reduced RINm5F cell viability (determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium (MTT) reduction assay) and de novo protein synthesis, as measured by incorporation of radiolabelled amino acids into perchloric acid-precipitable protein. Pretreatment of RINm5F cells with TGF beta 1 (10 pM) for 18 or 24 h, prior to the addition of either IL-1 beta or combined cytokines, prevented cytokine-induced inhibition of insulin secretion, protein synthesis and the loss of cell viability. TGF beta 1 pretreatment inhibited cytokine-induced expression and activity of nitric oxide synthase in RINm5F cells as determined by Western blotting and by cytosolic conversion of radiolabelled arginine into labelled citrulline and nitric oxide. Chemically generated superoxide also induced expression of nitric oxide synthase possibly due to direct activation of the nuclear transcription factor NF kappa B, an effect prevented by both an antioxidant and TGF beta 1 pretreatment. In conclusion, the mechanism of action of TGF beta 1 in blocking cytokine inhibitory effects was by preventing induction of nitric oxide synthase.

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Involvement of NADPH oxidase in oxidized LDL-induced upregulation of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.91023.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. E104-E111 ◽

Cited By ~ 26

Author(s):

Ruozhi Zhao ◽

Xiuli Ma ◽

Xueping Xie ◽

Garry X. Shen

Keyword(s):

Endothelial Cells ◽

Vascular Endothelial Cells ◽

Oxidized Ldl ◽

Plasminogen Activator Inhibitor ◽

Heat Shock Factor 1 ◽

Vascular Endothelial ◽

Plasminogen Activator Inhibitor 1 ◽

Induced Expression ◽

Activator Inhibitor ◽

Pai 1

Plasminogen activator inhibitor-1 (PAI-1) is implicated in thrombogenesis, inflammation, and extracellular matrix remodeling. Previous studies indicated that oxidized low-density lipoprotein (LDL) stimulated the generation of PAI-1 in vascular endothelial cells (EC). The present study demonstrated that LDL oxidized by copper, iron, or 3-morpholinosydnonimine increased the expression of NADPH oxidase (NOX) 2, PAI-1, and heat shock factor-1 (HSF1) in human umbilical vein EC or coronary artery EC compared with LDL or vehicle. Diphenyleneiodonium, a NOX inhibitor, prevented the increases of the expression of HSF1 and PAI-1 in EC induced by oxidized LDLs. Small-interference RNA (siRNA) for p22phox, an essential subunit of NOX, prevented oxidized LDL-induced expression of NOX2, HSF1, and PAI-1 in EC. HSF1 siRNA inhibited oxidized LDL-induced expression of PAI-1 and HSF1, but not NOX2, in EC. The binding of HSF1 to PAI-1 promoter and the activity of PAI-1 promoter in EC were enhanced by oxidized LDL. Butylated hydroxytulene, a potent antioxidant, inhibited oxidized LDL-induced release of hydrogen peroxide (H2O2) and the expression of NOX2, HSF1, and PAI-1 in EC. Treatment with H2O2 increased the abundance of NOX2, HSF1, and PAI-1 in EC. The results of the present study indicate that oxidized LDL-induced expression of NOX may lead to the elevated release of reactive oxygen species, the activation of HSF1, and the enhancement of the transcription of PAI-1 gene in cultured vascular EC.

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Evidence for the involvement of protein kinase activity in transforming growth factor-beta signal transduction.

Molecular and Cellular Biology ◽

10.1128/mcb.12.1.261 ◽

1992 ◽

Vol 12 (1) ◽

pp. 261-265 ◽

Cited By ~ 55

Author(s):

M Ohtsuki ◽

J Massagué

Keyword(s):

Protein Kinase C ◽

Growth Factor ◽

Protein Kinase ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

G1 Phase ◽

Tgf Beta ◽

Kinase C ◽

Growth Factor Beta ◽

Pai 1

Transforming growth factor-beta 1 (TGF-beta 1) rapidly increases the expression of junB transcription factor and plasminogen activator inhibitor-1 (PAI-1) and prevents the cell cycle-dependent phosphorylation of the RB retinoblastoma susceptibility gene product during late G1 phase in Mv1Lu lung epithelial cells. These responses are shown in this report to be blocked by the potent serine/threonine protein kinase inhibitor, H7, added with TGF-beta 1. Added alone, H7 does not alter the basal junB or PAI-1 mRNA levels, the deposition of PAI-1 into the extracellular matrix, or the phosphorylation of RB in late G1 phase, suggesting that this inhibitor does not have a general nonspecific effect on the cell. The analogs H8 and H9, which are preferential inhibitors of cyclic nucleotide-dependent protein kinases, are fivefold less potent than H7 as inhibitors of the TGF-beta response. The PAI-1 response to TGF-beta 1 is not affected by the simultaneous addition of staurosporine, which is a protein kinase C inhibitor, or by the prolonged preincubation of cells with phorbol 12-myristate 13-acetate, which down-regulates protein kinase C. The results suggest the possibility that H7 and its analogs block various early TGF-beta responses by inhibiting a protein serine/threonine kinase(s).

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