Transforming Growth Factor-β1 Has both Promoting and Inhibiting Effects on Induction of DNA Synthesis in Human Fibroblasts

Fukami, Junya; Tsuji, Kazue; Ueno, Akemi; Ide, Toshinori

doi:10.1006/excr.1995.1014

Cited by 17 publications

(11 citation statements)

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“…Indeed, NR3 cells are responsive to the regulatory influences of TGF‐β 1 when the cells are at confluence but are non‐responsive when they are actively growing (in logarithmic or exponential growth phase). These findings are in agreement with other studies which have shown that TGF‐β 1 can have both growth promoting or growth inhibitory effects within the same cells depending on the status of the cells' growth [Fukami et al, 1995; Goodman and Majeck, 1989]. TGF‐β 1 has been shown to be a bi‐functional response, density dependent regulator of vascular smooth muscle cells [Goodman and Majeck, 1989].…”

Section: Discussionsupporting

confidence: 90%

Transformation by H-ras can result in aberrant regulation of ornithine decarboxylase gene expression by transforming growth factor-?1

2001

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Inhibition of DNA synthesis and cell proliferation is frequently lost during malignant transformation and occasionally, tumour cell proliferation is actually stimulated by transforming growth factor beta(1) (TGF-beta(1)). The present study demonstrates a novel link between alterations in TGF-beta(1) regulation during cellular transformation and malignant conversion and the expression of ornithine decarboxylase (ODC) which is a key rate limiting activity in the biosynthesis of polyamines and which is an enzyme that plays an important role in cell growth and differentiation. H-ras transformed mouse 10T(1/2) cell lines of varying degrees of malignant potential were examined for possible TGF-beta(1)-mediated alterations in ODC expression. Selective induction of ODC gene expression occurred. This induction was dependent upon the cellular phenotype expressed and the mechanisms responsible for the regulation of the TGF-beta(1)-mediated alterations in ODC expression varied as a function of malignant potential. The TGF-beta(1)-mediated alterations in ODC gene expression involves de novo protein synthesis, transcriptional, and post-transcriptional events. Evidence is also presented to suggest a possible role for protein kinase C-mediated events, protein phosphatases, and G-protein-coupled events in the TGF-beta(1)-mediated regulation of ODC expression in H-ras transformed cells. Evidence is also presented to suggest a possible role for cellular polyamines in the TGF-beta(1)-mediated alterations in ODC expression in H-ras transformed cells. Additionally, alterations in cellular polyamines were shown to influence TGF-beta(1) gene expression in H-ras transformed cells and that these alterations occurred, in part, through post-transcriptional events. The TGF-beta(1)-mediated regulation of ODC expression in H-ras transformed cells of varying degrees of malignant potential appears to be complex, multifaceted, and interactive. This study illustrates the importance of TGF-beta(1)-mediated regulation of ODC expression as a result of H-ras mediated cellular transformation and malignant progression, and further suggests that this TGF-beta(1)-mediated regulation constitutes an integral part of an altered growth regulatory program.

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Section: Discussionsupporting

confidence: 90%

Transformation by H-ras can result in aberrant regulation of ornithine decarboxylase gene expression by transforming growth factor-?1

2001

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“…(B) S phase-dependent WRN focus formation. Normal primary fibroblasts (TIG-3) were incubated in low serum media for 48 hours and then stimulated to proliferate by exchanging with high serum media (Fukami et al, 1995). After then, these cells were treated by etoposide (30 μM) for 4 hours and immuno-staining was performed using anti-WRN and anti-phospho-DNA-PKcs (T2609) antibodies.…”

Section: Figuresmentioning

confidence: 99%

WRN participates in translesion synthesis pathway through interaction with NBS1

Kobayashi

Okui

Asaithamby

et al. 2010

Mechanisms of Ageing and Development

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Werner syndrome (WS), caused by mutation of the WRN gene, is an autosomal recessive disorder associated with premature aging and predisposition to cancer. WRN belongs to the RecQ DNA helicase family, members of which play a role in maintaining genome stability. Here, we demonstrate that WRN rapidly forms discrete nuclear foci in an NBS1-dependent manner following DNA damage. NBS1 physically interacts with WRN through its FHA domain, which interaction is important for the phosphorylation of WRN. WRN subsequently forms DNA damage-dependent foci during the S phase, but not in the G1 phase. WS cells exhibit an increase in spontaneous focus formation of pol η and Rad18, which are important for translesion synthesis (TLS). WRN also interacts with PCNA in the absence of DNA damage, but DNA damage induces the dissociation of PCNA from WRN, leading to the ubiquitination of PCNA, which is essential for TLS. This dissociation correlates with ATM/NBS1-dependent degradation of WRN. Moreover, WS cells show constitutive ubiquitination of PCNA and interaction between PCNA and Rad18 E3 ligase in the absence of DNA damage. Taken together, these results indicate that WRN participates in the TLS pathway to prevent genomic instability in an ATM/NBS1-dependent manner.

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“…This suggests that small amounts of TGF-ß promote RPE cell proliferation whereas higher concentrations of TGF-ß inhibit RPE proliferation. Such bifunctional effects of TGF-ß on the growth of RPE and other cell lines have been reported previously [8,13,17,18]. This effect may be due to (1) TGF-ß-mediated density-dependent apoptosis, (2) potentiation of the effect of other cytokines, such as PDGF [40], EGF [18], IGF [19] or FGF [17] by TGF-ß, or (3) the presence of low-affinity TGF-ß receptors mediating growth inhibition and high-affinity receptors mediating growth stimulation [41].…”

Section: Discussionmentioning

confidence: 82%

“…TGF-ß 1 , TGF-ß 2 and activin A are the only cytokines with a molecular weight 125 kDa that have been shown to inhibit RPE proliferation in vitro. The TGF-ß family includes over two dozen cytokines which can promote or inhibit the growth of a wide variety of cells, including RPE [8,[13][14][15][16][17][18][19]. These cytokines are disulfide-linked homodimers with molecular weights around 25 kDa in their active form [20].…”

Section: Discussionmentioning

confidence: 99%

“…The cells were treated with 3% hydrogen peroxide for 5 min to quench endogenous peroxidase activity and 1% bovine serum albumin (Sigma) to block nonspecific binding sites. The cells were incubated at 37°C for 1 h with a mixture of monoclonal antipan cytokeratin antibodies to cytokeratins 1, 4, 5,6,8,10,13,18 and 19 (Sigma). This antibody recognizes the major cytokeratines expressed by RPE both in quiescent state (cytokeratin 8, 18) and during cell proliferation (cytokeratin 19), and thus enabled us to differentiate RPE at the time of harvest and plating [11].…”

Section: Cytokeratin Stainingmentioning

confidence: 99%

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TGF Beta Secretion Modulates the Density-Dependent Growth of Pig Retinal Pigment Epithelium in vitro

Tezel¹,

Priore

1999

Ophthalmic Res

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Background: We aimed to identify the cytokine(s) responsible for the density-dependent growth regulation of pig retinal pigment epithelium (RPE) in vitro. Methods: Confluent monolayers of primary pig RPE were established on bovine corneal endothelial extracellular matrix-coated tissue culture well inserts wrapped with dialysis membranes with different molecular weight cutoffs (0.5–50 kDa). These confluent RPE monolayers were then cocultured with first passage porcine RPE plated at a density of 1 cell/mm², so that the newly plated RPE was bathed with different molecular weight fractions of the confluent cell media. Growth rates of the newly plated RPE were determined 72 h after plating and the molecular weight fraction of the confluent cell medium that inhibits the RPE proliferation was determined. First passage pig RPE (1 cell/mm²) were cocultured with confluent monolayers of primary pig RPE on inserts in the presence of different amounts of TGF-β neutralizing antibody (0.1–100 µg/ml). Growth rates of the newly plated RPE were calculated 72 h after plating to determine the antibody concentration that would maximize the growth rate of the newly plated RPE in the presence of an adjacent confluent RPE monolayer. Results: The growth rate of the newly plated RPE decreased when RPE were bathed with the 10- to 25-kDa fractions of medium from an adjacent confluent RPE monolayer. This growth inhibition reached statistical significance with the 25- to 50-kDa fractions (p < 0.05), and was abolished by adding pan-specific neutralizing antibody against TGF-β (0.1–5 µg/ml). Blocking greater amounts of TGF-β in the medium with higher doses of antibody (>10 µg/ml) also inhibited the growth of the newly plated RPE, in the presence or absence of a neighboring confluent cell layer. Conclusion: The TGF-β family of cytokines mediates the density-dependent growth suppression of RPE in vitro. Neutralizing the effect of these cytokines by adding anti-TGF-β antibodies can result in more rapid growth of the RPE in vivo.

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Transforming Growth Factor-β1 Has both Promoting and Inhibiting Effects on Induction of DNA Synthesis in Human Fibroblasts

Cited by 17 publications

References 0 publications

Transformation by H-ras can result in aberrant regulation of ornithine decarboxylase gene expression by transforming growth factor-?1

Transformation by H-ras can result in aberrant regulation of ornithine decarboxylase gene expression by transforming growth factor-?1

WRN participates in translesion synthesis pathway through interaction with NBS1

TGF Beta Secretion Modulates the Density-Dependent Growth of Pig Retinal Pigment Epithelium in vitro

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