Resveratrol Increases Serine<sup>15</sup>-Phosphorylated but Transcriptionally Impaired p53 and Induces a Reversible DNA Replication Block in Serum-Activated Vascular Smooth Muscle Cells

Haider, Ursula G. B.; Sorescu, Dan C.; Griendling, Kathy K.; Vollmar, Angelika M.; Dirsch, Verena M.

doi:10.1124/mol.63.4.925

Cited by 54 publications

(36 citation statements)

References 39 publications

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“…It is possible that resveratrol's activity in eliciting an S-phase arrest [23], in conjunction with reductions in lgs and pygoI, may affect the cellular distribution of β-catenin in a way that reduces Wnt signal throughput. The S-phase arrest mediated by resveratrol, confirmed here in RKO cells, occurs at lower concentrations than its cytotoxic and apoptotic effects [24][25][26][27][28]. Recently, it has been suggested that β-catenin transcriptional activity is regulated not only through the levels of protein degradation, but also via regulation of its nuclear localization [29].…”

Section: Discussionmentioning

confidence: 98%

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Hope

Planutis

Planutiene

et al. 2008

Mol. Nutr. Food Res.

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Resveratrol is a bioflavonoid which is known to inhibit cell proliferation and induce apoptosis in cancer cell lines at concentrations above 50uM. It also has colon cancer prevention activity in mouse models and possibly in humans. We have examined the effects of low concentrations of resveratrol on a specific signaling pathway, the Wnt pathway, which is activated in over 85% of sporadic colon cancers. Two colon cancer (HT29 and RKO) and one normal mucosa-derived (NCM460) cell lines were utilized. Cell proliferation was not affected by resveratrol at ≤40uM for HT29 and NCM460 and <20uM for RKO though Wnt signal throughput, as measured by a reporter construct, was reduced in RKO and NCM460 at concentrations as low as 10uM (p<0.001). This effect was most easily appreciated following Wnt pathway stimulation with Wnt3a conditioned medium and LEF1 or LEF1/ β-catenin transfection. Resveratrol did not inhibit Wnt throughput in mutationally activated HT29. Low concentrations of resveratrol significantly decreased the amount and proportion of β-catenin in the nucleus in RKO (p=0.002) and reduced the expression of lgs and pygoI, regulators of β-catenin localization in all cells lines. Thus, at low concentrations, in the absence of effects on cell proliferation, resveratrol significantly inhibits Wnt signaling in colon-derived cells which do not have a basally activated Wnt pathway. This inhibitory effect may be due in part to regulation of intracellular β-catenin localization.

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Section: Discussionmentioning

confidence: 98%

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Hope

Planutis

Planutiene

et al. 2008

Mol. Nutr. Food Res.

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“…Both Ang II and EGF are expressed in atherosclerotic lesions (Jiang et al, 2002). It is important to note that the concentrations of RV used to perform this study were not toxic for VSMCs (Haider et al, 2002(Haider et al, , 2003. Although little information is available about in vivo bioavailability of RV, there is some evidence that the amount of RV absorbed from the intestine may be sufficient to elicit biologic responses (Wu et al, 2001).…”

Section: Downloaded Frommentioning

confidence: 99%

“…Wallerath et al (2002) demonstrated that RV enhances expression and activity of endothelial nitric oxide synthase. Our group has recently shown that RV reversibly inhibits cell cycle progression in early S phase in calf serum-treated VSMC (Haider et al, 2003). In addition, an in vivo study revealed that RV attenuates intimal hyperplasia after endothelial denudation in an experimental rabbit model (Zou et al, 2000).…”

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confidence: 99%

Resveratrol Inhibits Angiotensin II- and Epidermal Growth Factor-Mediated Akt Activation: Role of Gab1 and Shp2

Haider¹,

Roos²,

Kontaridis³

et al. 2005

Mol Pharmacol

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trans-Resveratrol (RV), a polyphenolic stilbene derivative found in grape skin and other food products, has been proposed to exert beneficial effects in cardiovascular disease. Our group has shown previously that RV inhibits angiotensin II (Ang II)-induced Akt activation and, consequently, vascular smooth muscle cell (VSMC) hypertrophy. In this work, to identify the molecular target of RV, we investigated the impact of RV on early signaling cascades in rat aortic VSMCs triggered by Ang II and epidermal growth factor (EGF). We show that RV does not influence Ang II-mediated transactivation of EGF-receptor but potently inhibits EGF-induced phosphorylation of Akt kinase, suggesting that RV acts downstream of EGF-receptor transactivation in VSMCs. Recent evidence indicates that the adapter molecule Gab1, together with the protein tyrosine phosphatase Shp2, is critically involved in regulating the strength and duration of phosphatidylinositol-3-kinase (PI3K) and Akt activation upon EGF stimulation in fibroblasts. Our results show that stimulation of VSMCs with EGF as well as Ang II leads to a rapid tyrosine phosphorylation of Gab1 and its association with the p85 subunit of PI3K. RV attenuates these processes. Experiments performed in Shp2-deficient fibroblasts revealed that RV does not inhibit EGF-stimulated Akt activation in these cells, suggesting that Shp2 is necessary for the inhibitory effect of RV on the PI3K/Akt pathway. Furthermore, RV treatment activates Shp2. We therefore propose that RV blocks Akt activation in Ang II-and EGF-stimulated VSMCs by activating Shp2, thus preventing interaction between Gab1 and PI3K that is necessary for further signal transduction.

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“…Protein isolation and immunoblotting were performed essentially as described by Haider et al 17 All antibodies used were from New England BioLabs with the exception of anti-␣-tubulin (Santa Cruz Biotechnology Inc) and a horseradish peroxidase-conjugated goat antimouse secondary antibody (Upstate). Proteins were visualized using the ECL reagent and an LAS-3000 luminescent image analyzer (Fujifilm) with AIDA software (Raytest).…”

Section: Sds-page and Immunoblottingmentioning

confidence: 99%

Indirubin-3′-Monoxime Blocks Vascular Smooth Muscle Cell Proliferation by Inhibition of Signal Transducer and Activator of Transcription 3 Signaling and Reduces Neointima Formation In Vivo

Schwaiberger

Heiss

Cabaravdic

et al. 2010

ATVB

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Objective-Our goal was to examine the influence of indirubin-3Ј-monoxime (I3MO), a natural product-derived cyclin-dependent kinase inhibitor, on vascular smooth muscle cell (VSMC) proliferation in vitro, experimentally induced neointima formation in vivo, and related cell signaling pathways. Methods and Results-I3MO dose-dependently inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation by arresting cells in the G 0 /G 1 phase of the cell cycle as assessed by 5-bromo-2Ј-deoxyuridine incorporation and flow cytometry. PDGF-induced activation of the kinases Akt, Erk1/2, and p38 MAPK was not affected. In contrast, I3MO specifically blocked PDGF-, interferon-␥-, and thrombin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Human endothelial cells (EA.hy926) responded to I3MO with increased endothelial nitric oxide synthase activity as assessed via Key Words: indirubin Ⅲ vascular smooth muscle cell Ⅲ proliferation Ⅲ neointima Ⅲ STAT3 R estenosis is the major factor hampering the beneficial effect of angioplasty and stenting. Vascular smooth muscle cell (VSMC) proliferation, next to local vascular inflammation, is a critical factor in neointima formation and vascular lumen loss during restenosis. Thus, one current strategy to maintain proper vascular function after angioplasty is to inhibit VSMC proliferation by targeting cell cycle regulation, eg, by drug-eluting stents. 2,3 Two products, the rapamycin-eluting Cypher stent and the paclitaxel-eluting Taxus stent, were approved by the US Food and Drug Administration in 2003 and 2004, respectively. Although successfully introduced into the market, there are now concerns about an increased risk of late stent thrombosis. 4 Thus, compounds inhibiting neointima formation with mechanisms differing from those of rapamycin and paclitaxel 5 may have the potential to be efficient with fewer side effects.Indirubin, a red isomer of indigo, is the active ingredient of the traditional Chinese medicinal formulation Danggui Longhui Wan, used against chronic myelocytic leukemia. 6 Enzyme-based in vitro studies have indicated that indirubin and its derivatives are potent inhibitors of the cyclindependent kinases (CDKs) 1, 2, 4, and 5. 6 -9 Furthermore, different indirubin derivatives showed antitumor activity in several human cancer cells. 6,10 -14 Moreover, for indirubin-3Ј-monoxime (I3MO), an in vitro antiinflammatory and anticancer activity had been described on the basis of the inhibition of tumor necrosis factor-induced nuclear factor B activation and the subsequent suppression of antiapoptotic and proproliferative gene expression. 14 The aim of this study was to investigate the potential use of I3MO in the prevention of restenosis. We therefore analyzed a possible effect on platelet-derived growth factor (PDGF)- MethodsAn expanded Methods section can be found in the Supplemental Data, available online at http://atvb.ahajournals.org. Cell CultureVSMCs were isolated from male Sprague-Dawley rat thoracic aortas by enzyma...

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Resveratrol Increases Serine¹⁵-Phosphorylated but Transcriptionally Impaired p53 and Induces a Reversible DNA Replication Block in Serum-Activated Vascular Smooth Muscle Cells

Cited by 54 publications

References 39 publications

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Resveratrol Inhibits Angiotensin II- and Epidermal Growth Factor-Mediated Akt Activation: Role of Gab1 and Shp2

Indirubin-3′-Monoxime Blocks Vascular Smooth Muscle Cell Proliferation by Inhibition of Signal Transducer and Activator of Transcription 3 Signaling and Reduces Neointima Formation In Vivo

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Resveratrol Increases Serine15-Phosphorylated but Transcriptionally Impaired p53 and Induces a Reversible DNA Replication Block in Serum-Activated Vascular Smooth Muscle Cells

Cited by 54 publications

References 39 publications

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: Implications for colon cancer prevention

Resveratrol Inhibits Angiotensin II- and Epidermal Growth Factor-Mediated Akt Activation: Role of Gab1 and Shp2

Indirubin-3′-Monoxime Blocks Vascular Smooth Muscle Cell Proliferation by Inhibition of Signal Transducer and Activator of Transcription 3 Signaling and Reduces Neointima Formation In Vivo

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Resveratrol Increases Serine¹⁵-Phosphorylated but Transcriptionally Impaired p53 and Induces a Reversible DNA Replication Block in Serum-Activated Vascular Smooth Muscle Cells