Hyperoxia inhibits proliferation of Mv1Lu epithelial cells independent of TGF-β signaling

1999 ◽  
Vol 277 (6) ◽  
pp. L1172-L1178 ◽  
Author(s):  
Raymond C. Rancourt ◽  
Rhonda J. Staversky ◽  
Peter C. Keng ◽  
Michael A. O'reilly
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Transforming Growth Factor Β ◽  
S Phase ◽  
Epithelial Cell Line ◽  
Type I ◽  
High Concentrations ◽  
Simple Growth

High concentrations of O2 inhibit epithelial cell proliferation that resumes on recovery in room air. To determine whether growth arrest is mediated by transforming growth factor-β (TGF-β), changes in cell proliferation during exposure to hyperoxia were assessed in the mink lung epithelial cell line Mv1Lu and the clonal variant R1B, which is deficient for the type I TGF-β receptor. Mv1Lu cells treated with TGF-β accumulated in the G1 phase of the cell cycle as determined by propidium iodide staining, whereas proliferation of R1B cells was unaffected by TGF-β. In contrast, hyperoxia inhibited proliferation of both cell lines within 24 h of exposure through an accumulation in the S phase. Mv1Lu cells treated with TGF-β and exposed to hyperoxia accumulated in the G1 phase, suggesting that TGF-β can inhibit the S phase accumulation observed with hyperoxia alone. Cyclin A was detected in cultures exposed to room air or growth arrested by hyperoxia while decreasing in cells growth arrested in the G1 phase by TGF-β. Finally, hyperoxia failed to activate a TGF-β-dependent transcriptional reporter in both Mv1Lu and R1B cells. These findings reveal that simple growth arrest by hyperoxia involves a defect in S phase progression that is independent of TGF-β signaling.

scholarly journals MicroRNA-224 Is Involved in Transforming Growth Factor-β-Mediated Mouse Granulosa Cell Proliferation and Granulosa Cell Function by Targeting Smad4

2010 ◽  
Vol 24 (3) ◽  
pp. 540-551 ◽  
Author(s):  
Guidong Yao ◽  
Mianmian Yin ◽  
Jie Lian ◽  
Hui Tian ◽  
Lin Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Granulosa Cell ◽  
Transforming Growth Factor ◽  
Cell Function ◽  
Ectopic Expression ◽  
Follicular Development ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Mrna Levels ◽  
Tgf Β1

Abstract Many members of the TGF-β superfamily are indicated to play important roles in ovarian follicular development, such as affecting granulosa cell function and oocyte maturation. Abnormalities associated with TGF-β1 signaling transduction could result in female infertility. MicroRNAs (miRNAs), as small noncoding RNAs, were recently found to regulate gene expression at posttranscriptional levels. However, little is known about the role of miRNAs in TGF-β-mediated granulosa cell proliferation and granulosa cell function. In this study, the miRNA expression profiling was identified from TGF-β1-treated mouse preantral granulosa cells (GCs), and three miRNAs were found to be significantly up-regulated and 13 miRNAs were down-regulated. Among up-regulated miRNAs, miR-224 was the second most significantly elevated miRNA. This up-regulation was attenuated by treatment of GCs with SB431542 (an inhibitor of TGFβ superfamily type I receptors, thus blocking phosphorylation of the downstream effectors Smad2/3), indicating that miR-224 expression was regulated by TGF-β1/Smads pathway. The ectopic expression of miR-224 can enhance TGF-β1-induced GC proliferation through targeting Smad4. Inhibition of endogenous miR-224 partially suppressed GC proliferation induced by TGF-β1. In addition, both miR-224 and TGF-β1 can promote estradiol release from GC, at least in part, through increasing CYP19A1 mRNA levels. This is the first demonstration that miRNAs can control reproductive functions resulting in promoting TGF-β1-induced GC proliferation and ovarian estrogen release. Such miRNA-mediated effects could be potentially used for regulation of reproductive processes or for treatment of reproductive disorders.

scholarly journals Rapamycin Potentiates Transforming Growth Factor β-Induced Growth Arrest in Nontransformed, Oncogene-Transformed, and Human Cancer Cells

2002 ◽  
Vol 22 (23) ◽  
pp. 8184-8198 ◽  
Author(s):  
Brian K. Law ◽  
Anna Chytil ◽  
Nancy Dumont ◽  
Elizabeth G. Hamilton ◽  
Mary E. Waltner-Law ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cancer Cells ◽  
Cell Lines ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Growth Arrest ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Human Carcinoma ◽  
Cdk2 Activity

ABSTRACT Transforming growth factor β (TGF-β) induces cell cycle arrest of most nontransformed epithelial cell lines. In contrast, many human carcinomas are refractory to the growth-inhibitory effect of TGF-β. TGF-β overexpression inhibits tumorigenesis, and abolition of TGF-β signaling accelerates tumorigenesis, suggesting that TGF-β acts as a tumor suppressor in mouse models of cancer. A screen to identify agents that potentiate TGF-β-induced growth arrest demonstrated that the potential anticancer agent rapamycin cooperated with TGF-β to induce growth arrest in multiple cell lines. Rapamycin also augmented the ability of TGF-β to inhibit the proliferation of E2F1-, c-Myc-, and V12H-Ras-transformed cells, even though these cells were insensitive to TGF-β-mediated growth arrest in the absence of rapamycin. Rapamycin potentiation of TGF-β-induced growth arrest could not be explained by increases in TGF-β receptor levels or rapamycin-induced dissociation of FKBP12 from the TGF-β type I receptor. Significantly, TGF-β and rapamycin cooperated to induce growth inhibition of human carcinoma cells that are resistant to TGF-β-induced growth arrest, and arrest correlated with a suppression of Cdk2 kinase activity. Inhibition of Cdk2 activity was associated with increased binding of p21 and p27 to Cdk2 and decreased phosphorylation of Cdk2 on Thr160. Increased p21 and p27 binding to Cdk2 was accompanied by decreased p130, p107, and E2F4 binding to Cdk2. Together, these results indicate that rapamycin and TGF-β cooperate to inhibit the proliferation of nontransformed cells and cancer cells by acting in concert to inhibit Cdk2 activity.

scholarly journals Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest.

1991 ◽  
Vol 11 (3) ◽  
pp. 1185-1194 ◽  
Author(s):  
P H Howe ◽  
G Draetta ◽  
E B Leof
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Transforming Growth Factor Beta ◽  
Kinase Activity ◽  
Transforming Growth Factor ◽  
S Phase ◽  
Epithelial Cell Proliferation ◽  
Tgf Beta ◽  
Growth Factor Beta

Transforming growth factor beta 1 (TGF beta 1) is a potent inhibitor of epithelial cell proliferation. We present data which indicate that epithelial cell proliferation is inhibited when TGF beta 1 is added throughout the prereplicative G1 phase. Cultures become reversibly blocked in late G1 at the G1/S-phase boundary. The inhibitory effects of TGF beta 1 on cell growth occur in the presence of the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. Associated with this inhibitory effect is a decrease in the phosphorylation and histone H1 kinase activity of the p34cdc2 protein kinase. These data suggest that TGF beta 1 growth inhibition in epithelial cells involves the regulation of p34cdc2 activity at the G1/S transition.

scholarly journals Autocrine TGFβ1 Opposes Exogenous TGFβ1-Induced Cell Migration and Growth Arrest through Sustainment of a Feed-Forward Loop Involving MEK-ERK Signaling

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1357
Author(s):  
Hendrik Ungefroren ◽  
Jessica Christl ◽  
Caroline Eiden ◽  
Ulrich F. Wellner ◽  
Hendrik Lehnert ◽  
...  
Keyword(s):  
Cell Motility ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Ectopic Expression ◽  
Growth Arrest ◽  
Transforming Growth Factor Β ◽  
Erk Signaling ◽  
Ductal Adenocarcinoma ◽  
Type I ◽  
Cyclin Dependent Kinase Inhibitor

Autocrine transforming growth factor β (aTGFβ) has been implicated in the regulation of cell invasion and growth of several malignant cancers such as pancreatic ductal adenocarcinoma (PDAC) or triple-negative breast cancer (TNBC). Recently, we observed that endogenous TGFB1 can inhibit rather than stimulate cell motility in cell lines with high aTGFβ production and mutant KRAS, i.e., Panc1 (PDAC) and MDA-MB-231 (TNBC). The unexpected anti-migratory role prompted us to evaluate if aTGFβ1 may be able to antagonize the action of exogenous (recombinant human) TGFβ (rhTGFβ), a well-known promoter of cell motility and growth arrest in these cells. Surprisingly, RNA interference-mediated knockdown of the endogenous TGFB1 sensitized genes involved in EMT and cell motility (i.e., SNAI1) to up-regulation by rhTGFβ1, which was associated with a more pronounced migratory response following rhTGFβ1 treatment. Ectopic expression of TGFB1 decreased both basal and rhTGFβ1-induced migratory activities in MDA-MB-231 cells but had the opposite effect in Panc1 cells. Moreover, silencing TGFB1 reduced basal proliferation and enhanced growth inhibition by rhTGFβ1 and induction of cyclin-dependent kinase inhibitor, p21WAF1. Finally, we show that aTGFβ1 promotes MEK-ERK signaling and vice versa to form a self-perpetuating feedforward loop that is sensitive to SB431542, an inhibitor of the TGFβ type I receptor, ALK5. Together, these data suggest that in transformed cells an ALK5-MEK-ERK-aTGFβ1 pathway opposes the promigratory and growth-arresting function of rhTGFβ1. This observation has profound translational implications for TGFβ signaling in cancer.

scholarly journals SPARC Inhibits Epithelial Cell Proliferation in Part through Stimulation of the Transforming Growth Factor-β–Signaling System

2003 ◽  
Vol 14 (10) ◽  
pp. 3977-3988 ◽  
Author(s):  
Barbara J. Schiemann ◽  
Jason R. Neil ◽  
William P. Schiemann
Keyword(s):  
Cell Proliferation ◽  
Epithelial Cell ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Secreted Protein ◽  
Epithelial Cell Proliferation ◽  
Signaling System ◽  
Smad2 Phosphorylation ◽  
Β Receptor ◽  
Dependent Pathway

Secreted protein, acidic and rich in cysteine (SPARC) is a multifunctional secreted protein that regulates cell–cell and cell–matrix interactions, leading to alterations in cell adhesion, motility, and proliferation. Although SPARC is expressed in epithelial cells, its ability to regulate epithelial cell growth remains largely unknown. We show herein that SPARC strongly inhibited DNA synthesis in transforming growth factor (TGF)-β–sensitive Mv1Lu cells, whereas moderately inhibiting that in TGF-β–insensitive Mv1Lu cells (i.e., R1B cells). Overexpression of dominant-negative Smad3 in Mv1Lu cells, which abrogated growth arrest by TGF-β, also attenuated growth arrest stimulated by SPARC. Moreover, the extracellular calcium-binding domain of SPARC (i.e., SPARC-EC) was sufficient to inhibit Mv1Lu cell proliferation but not that of R1B cells. Similar to TGF-β and thrombospondin-1, treatment of Mv1Lu cells with SPARC or SPARC-EC stimulated Smad2 phosphorylation and Smad2/3 nuclear translocation: the latter response to all agonists was abrogated in R1B cells or by pretreatment of Mv1Lu cells with neutralizing TGF-β antibodies. SPARC also stimulated Smad2 phosphorylation in MB114 endothelial cells but had no effect on bone morphogenetic protein-regulated Smad1 phosphorylation in either Mv1Lu or MB114 cells. Finally, SPARC and SPARC-EC stimulated TGF-β–responsive reporter gene expression through a TGF-β receptor- and Smad2/3-dependent pathway in Mv1Lu cells. Collectively, our findings identify a novel mechanism whereby SPARC inhibits epithelial cell proliferation by selectively commandeering the TGF-β signaling system, doing so through coupling of SPARC-EC to a TGF-β receptor- and Smad2/3-dependent pathway.

Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta

1988 ◽  
Vol 8 (8) ◽  
pp. 3088-3093
Author(s):  
R J Coffey ◽  
C C Bascom ◽  
N J Sipes ◽  
R Graves-Deal ◽  
B E Weissman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Cell Line ◽  
Tgf Beta ◽  
Growth Factor Beta ◽  
Posttranscriptional Level

Transforming growth factor beta (TGF beta) is a potent inhibitor of epithelial cell proliferation. A nontumorigenic epidermal growth factor (EGF)-dependent epithelial cell line, BALB/MK, is reversibly growth arrested by TGF beta. TGF beta will also abrogate EGF-stimulated mitogenesis of quiescent BALB/MK cells. Increased levels of calcium (greater than 1.0 mM) will induce differentiation in BALB/MK cells; in contrast, TGF beta-mediated growth inhibition does not result in induction of terminal differentiation. In the present study, the effects of TGF beta and calcium on growth factor-inducible gene expression were examined. TGF beta markedly decreased c-myc and KC gene expression in rapidly growing BALB/MK cells and reduced the EGF induction of c-myc and KC in a quiescent population of cells. TGF beta exerted its control over c-myc expression at a posttranscriptional level, and this inhibitory effect was dependent on protein synthesis. TGF beta had no effect on c-fos gene expression, whereas 1.5 mM calcium attenuated EGF-induced c-fos expression in quiescent cells. Expression of beta-actin, however, was slightly increased in both rapidly growing and EGF-restimulated quiescent BALB/MK cells treated with TGF beta. Thus, in this system, TGF beta selectively reduced expression of certain genes associated with cell proliferation (c-myc and KC), and at least part of the TGF beta effect was at a posttranscriptional level.

Transforming growth factor beta 1 inhibition of p34cdc2 phosphorylation and histone H1 kinase activity is associated with G1/S-phase growth arrest

1991 ◽  
Vol 11 (3) ◽  
pp. 1185-1194
Author(s):  
P H Howe ◽  
G Draetta ◽  
E B Leof
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Transforming Growth Factor Beta ◽  
Kinase Activity ◽  
Transforming Growth Factor ◽  
S Phase ◽  
Epithelial Cell Proliferation ◽  
Tgf Beta ◽  
Growth Factor Beta

Transforming growth factor beta 1 (TGF beta 1) is a potent inhibitor of epithelial cell proliferation. We present data which indicate that epithelial cell proliferation is inhibited when TGF beta 1 is added throughout the prereplicative G1 phase. Cultures become reversibly blocked in late G1 at the G1/S-phase boundary. The inhibitory effects of TGF beta 1 on cell growth occur in the presence of the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole. Associated with this inhibitory effect is a decrease in the phosphorylation and histone H1 kinase activity of the p34cdc2 protein kinase. These data suggest that TGF beta 1 growth inhibition in epithelial cells involves the regulation of p34cdc2 activity at the G1/S transition.

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