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Integrin Vß3 contains a receptor site for resveratrol

Hung-Yun Lin^*, Lawrence Lansing, Jean-Michel Merillon, Faith B. Davis^,1, Heng-Yuan Tang^*, Ai Shih, Xavier Vitrac, Stephanie Krisa, Travis Keating^*, H. James Cao, Joel Bergh, Steven Quackenbush and Paul J. Davis^*,,,||

^* Stratton Veterans Affairs Medical Center and

Ordway Research Institute, Albany, New York, USA;

Laboratoire de Mycologie et Biotechnologie Vegetale, Université de Bordeaux, Bordeaux, Cedex, France; and

Albany Medical College and

^|| Wadsworth Center, New York State Department of Health, Albany, New York, USA

¹Correspondence: Ordway Research Institute, 150 New Scotland Ave., Albany, NY 12208, USA. E-mail: fdavis{at}ordwayresearch.org

ABSTRACT

Resveratrol is a naturally occurring polyphenol, which causes apoptosis in cultured cancer cells. We describe a cell surface resveratrol receptor on the extracellular domain of hetero-dimeric Vß3 integrin in MCF-7 human breast cancer cells. This receptor is linked to induction by resveratrol of extracellular-regulated kinases 1 and 2 (ERK1/2)- and serine-15-p53-dependent phosphorylation leading to apoptosis. The integrin receptor is near the Arg-Gly-Asp (RGD) recognition site on the integrin; an integrin-binding RGD peptide inhibits induction by resveratrol of ERK1/2- and p53-dependent apoptosis. Antibody (Ab) to integrin Vß3, but not to Vß5, inhibits activation by resveratrol of ERK1/2 and p53 and consequent apoptosis in estrogen receptor- (ER) positive MCF-7, and ER-negative MDA-MB231 cells. Resveratrol is displaced from the purified integrin by an RGD, but not RGE, peptide, and by Vß3 integrin-specific Ab. Resveratrol action is blocked by siRNAß3, but not by siRNAV. [¹⁴C]-Resveratrol binds to commercially purified integrin Vß3 and to Vß3 prepared from MCF-7 cells; binding of [¹⁴C]-resveratrol to the ß3, but not to the V monomer, is displaced by unlabeled resveratrol. In conclusion, binding of resveratrol to integrin Vß3, principally to the ß3 monomer, is essential for transduction of the stilbene signal into p53-dependent apoptosis of breast cancer cells.—Lin, H.-Y., Lansing, L., Merillon, J.-M., Davis, F. B., Tang, H.-Y., Shih, A., Vitrac, X., Krisa, S., Keating, T., Cao, H. J., Bergh, J., Quackenbush, S., Davis, P. J. Integrin Vß3 contains a receptor site for resveratrol.

Key Words: resveratrol • integrin Vß3 • apoptosis • breast cancer cell • extracellular-regulated kinases 1 and 2

THE STILBENE RESVERATROL exhibits properties of cancer prevention and apoptosis induction in human cancer cells (1) . In addition to its anticancer properties, resveratrol also has protective cardiovascular effects (2) and may be neuroprotective (3) . We and others have reported that resveratrol induces p53-dependent apoptosis in several cancer cell lines, and the signal transduction pathways implicated in resveratrol action include those of extracellular-regulated kinases 1 and 2 (ERK1/2), p38 kinase, and Jun N-terminal kinase (JNK) (4 5 6) . However, the initial steps in the cellular action of resveratrol as an antitumor agent are incompletely understood and a cellular receptor site at which the resveratrol signal is initiated has not been described. Resveratrol is regarded as a phytoestrogen and resembles estrogen in structure to some extent (7) . The nuclear estrogen receptor, however, has a low (micromolar range) affinity for resveratrol (8) . For this study we have chosen two breast cancer cell lines, MCF-7 cells with ER and wild-type p53, and MDA-MB231 cells that lack ER and contain a mutant p53 (9) . We have compared the effects of resveratrol in these two cell lines.

The integrins are heterodimeric structural plasma membrane glycoproteins whose extracellular domains bind to matrix proteins and other extracellular factors (10) . The intracellular domain of certain integrins, such as integrin Vß3, may activate ERK1/2 (11) . Nonpeptide integrin antagonist peptides, designed to mimic the integrin adhesion recognition sequence, RGD (Arg-Gly-Asp), have displayed efficacy in the treatment of cancer (12) . In contrast, RGE (Arg-Gly-Glut) peptides do not bind to the integrin and are ineffective in physiological models (11) . Because the actions of resveratrol on ERK1/2 activation take place in as early as 30–60 min (13) , we examined the possibility that resveratrol may initiate its ERK1/2-mediated cellular effects at an integrin in the plasma membrane of breast cancer cells.

MATERIALS AND METHODS

Cell culture
MCF-7 cells, which are ER-positive, were cultured in phenol red-free Dulbecco’s modified Eagle medium (DMEM) with 5% FBS (14) , and ER-negative MDA-MB231 cells were cultured in DMEM with 10% serum. Prior to study, cells were placed in medium supplemented with 0.25% hormone-stripped serum for 48 h, as we have previously described (4) .

MATERIALS

RGD and RGE peptides and resveratrol were obtained from Sigma-Aldrich (St. Louis, MO, USA) and purified integrin Vß3 from Chemicon (Temecula, CA, USA). Antibodies to integrins Vß3 and Vß5, and to V and ß3 monomers, were from Santa Cruz (Santa Cruz, CA, USA), as were antibodies to polyclonal antiserine 15-p53 (pSer15-p53) and antiphosphorylated extracellular-regulated kinases 1 and 2 (ERK1/2). Antilamin (Lamin B), used for verification of nuclear fractions, was obtained from Calbiochem (San Diego, CA, USA), and secondary antibodies were obtained from Dako (Carpinteria, CA, USA). Apoptosis was determined by nucleosome ELISA (Oncogene Research Products, Cambridge, MA, USA) after 24 h of resveratrol treatment. Band intensities from immunoblots were quantitated with the VersaDoc 5000 Imaging System (Bio-Rad Laboratories, Hercules, CA, USA).

Transfection with siRNA
MCF-7 cells were plated in 10 cm dishes (150,000 cells/dish) and incubated for 24 h in phenol red-free DMEM with 10% FBS. Cells were then rinsed in OptiMEM (Invitrogen/Life Technologies, Inc., Grand Island, NY, USA) and transfected with siRNA (100 nM final concentration) for V or ß3 (Ambion, Inc., Austin, TX, USA), or with a scrambled siRNA as a negative control. Four hours after transfection, growth medium containing 10% FBS was added to each sample and the cultures incubated overnight. The cells were then rinsed with PBS and placed in serum-free DMEM for 48 h prior to treatment. Plasma membrane fractions of transfected cells were subjected to PAGE and the proteins were studied with antibodies to V or ß3 monomers to demonstrate the effect of the transfections on plasma membrane Vß3 integrin levels.

Preparation of cell fractions
Nuclear fractions of MCF-7 and MDA-MB231 cells were prepared by our previously described method (15) . Plasma membrane fractions of MCF-7 cells were prepared by the method of Castro et al. (16) .

Studies of [¹⁴C]-resveratrol binding to cultured cell plasma membranes and to purified integrin Vß3
[¹⁴C]-trans-resveratrol was prepared by authors Vitrac et al. (17) from grape cell suspension cultures using an L-[U-ring-¹⁴C]-phenylalanine precursor at a specific activity of 400 mCi·mmol^–1. The specific activity of the labeled resveratrol was 9.9 µCi/mg. MCF-7 cell plasma membranes (50 µg) or purified integrin Vß3 (1.8 µg) were incubated with [¹⁴C]-resveratrol (10 µM) for 30 min at 20°C, followed by solubilization with nonionic detergent and separation of protein components by 5% nondenaturing PAGE. Proteins in one-half of the gel, including one integrin and one membrane sample, were then transferred to nitrocellulose and subjected to Western blotting with Vß3 Ab. Immunoreactive proteins were detected by chemiluminescence. Identification of V and ß3 monomers in Western blots was by molecular weights. The remaining integrin and plasma membrane samples on the original gel were dried and exposed to Imaging Screen K (Bio-Rad) for study by laser densitometry to quantitate protein radiolabeling.

In resveratrol displacement studies, purified integrin Vß3 was incubated with 10 µM [¹⁴C]-resveratrol for 30 min at room temperature. In selected samples, 1 or 10 µM unlabeled resveratrol was also added for 30 min at room temperature. Samples were separated in 5% native gels, which were then dried and analyzed by radioautography.

RESULTS

Resveratrol-induced p53 and ERK1/2 activation and apoptosis are blocked by an RGD recognition site peptide
To examine the role of plasma membrane integrin Vß3 in the action of resveratrol, estrogen receptor (ER)-positive breast cancer MCF-7 cells were treated with 10 µM resveratrol in the presence or absence of an integrin Vß3 RGD recognition site peptide, 5–500 nM. Serine-15 phosphorylated p53 (pSer15-p53) increased in the nuclei of resveratrol-treated cells, as did phosphorylated ERK1 and ERK2, indicating activation of this pathway (Fig. 1 A). Apoptosis of cells was induced, shown by the collective results of three nucleosome ELISA studies. The RGD peptide inhibited resveratrol-induced ERK1/2 activation, phosphorylation of Ser-15-p53, and apoptosis in a concentration-dependent manner. An inactive RGE peptide, however, which does not bind to integrin Vß3, had no inhibitory effect.

View larger version (21K): [in this window] [in a new window]   Figure 1. A) Integrin Vß3 is a binding site for resveratrol. MCF-7 cells were treated for 4 h with resveratrol (RV, 10 µM) in the presence or absence of RGD peptide (5–500 nM) or RGE peptide (500 nM). Nucleoproteins of treated cell samples were prepared, separated by gel electrophoresis, and immunoblotted with antibodies to serine-15-phosphorylated 53 (pSer15-p53) or phosphorylated ERK1/2 (pERK1/2). Resveratrol-induced ERK1/2 activation and pSer15-p53 phosphorylation were inhibited by the RGD peptide, whereas the control RGE peptide did not affect resveratrol-induced ERK1/2 activation or serine phosphorylation of p53. Immunoblots shown in the figures are representative of three experiments, and the upper graph shows the mean ± SEM of change from control image intensities normalized to a value of 1. In this and subsequent figures a lamin (Lamin B) immunoblot provides a control for loading of aliquots of nuclear fractions. MCF-7 cells treated for 24 h in the same manner were studied by nucleosome ELISA as a measure of apoptosis. The lower graph summarizes the results of three experiments and shows apoptosis induced by resveratrol and progressive inhibition of apoptosis by increasing concentrations of the RGD peptide, while the RGE peptide did not inhibit apoptosis. B) Ab to integrin Vß3 inhibits resveratrol-induced activation of ERK1/2, p53 phosphorylation and apoptosis of breast cancer cells. MCF-7 cells were treated with either anti-Vß3 (1–20 µg/ml) or anti-Vß5 (20 µg/ml) for 24 h with or without resveratrol (RV, 10 µM) added for the last 4 h. Anti Vß3 and anti-Vß5, each alone, was used as a negative control. Resveratrol-induced ERK1/2 activation and Ser-15-p53 phosphorylation were inhibited by anti-Vß3, 10–20 µg/ml, but not by Ab to Vß5 (20 µg/ml). The upper graph shows the increase in pERK1/2 and pSer15-p53 band intensities (mean±SE) in three similar experiments, and the lower graph shows the increase in apoptosis with resveratrol, measured by nucleosome ELISA. Inhibition of these effects by the addition of Vß3 Ab, but not Vß5 Ab, in three experiments, is also shown. A similar pattern of responses was seen in changes of pSer15-p53 levels, as shown by a representative immunoblot from three experiments. C) MDA-MB231 cells were treated with either anti-Vß3 (10–3–0.1 µg/ml) or anti-Vß5 (0.1 µg/ml) for 24 h with or without resveratrol (10 µM) for the last 4 h. Anti-Vß3 and anti-Vß5, in the absence of resveratrol, were used as negative controls. Resveratrol-induced ERK1/2 activation, serine phosphorylation of p53, and apoptosis were progressively inhibited by increasing concentrations of anti-Vß3 but not inhibited by Vß5 Ab.

Further evidence to support the role of Vß3 in the action of resveratrol is presented in Fig. 1B . Resveratrol-induced ERK1/2 activation, p53 phosphorylation, and apoptosis in MCF-7 cells were progressively inhibited by increasing concentrations of Ab to Vß3 but were not affected by anti-Vß5 (Fig. 1B ). In ER-negative MDA-MB231 breast cancer cells, resveratrol-induced ERK1/2 activation, p53 phosphorylation, and apoptosis were inhibited by even smaller concentrations of Vß3 Ab than those used with MCF-7 cells (Fig. 1C ) but were not inhibited by anti-Vß5. This study, in demonstrating the action of resveratrol in ER-negative MDA-MB231 cells, indicates that resveratrol action is independent of ER. In addition, the results demonstrate that the presence of mutant p53 in MDA-MB231 cells does not inhibit the induction of apoptosis and serine-15 p53 phosphorylation in response to resveratrol.

That integrin Vß3, principally the ß3 component, contains the binding site or principal contact points for resveratrol was further supported by the results of experiments using small interfering RNA (siRNA) of integrin Vß3. Transfection of MCF-7 cells with siRNA of V or ß3 resulted in decreased cellular abundance of V or ß3, respectively (Fig. 2 A). However, only siRNA knockdown of ß3 reduced resveratrol-induced ERK1/2 activation and Ser-15 p53 phosphorylation. These results indicated that only the ß3 monomer of integrin Vß3 was essential for activation of ERK1/2 by resveratrol, leading to serine-15 phosphorylation of p53 and induction of apoptosis by the stilbene.

View larger version (14K): [in this window] [in a new window]   Figure 2. A) Transfection of siRNA of the ß3 component of the integrin blocks resveratrol action in MCF-7 cells. Cells were exposed for 48 h to either scrambled RNA (scRNA) or small interfering RNA (siRNA) for integrin V or integrin ß3 and treated with or without resveratrol (10 µM) for the last 4 h. Resveratrol-induced ERK1/2 activation and p53 serine-15 phosphorylation, shown by immunoblots of nucleoproteins, were inhibited by integrin ß3 siRNA but not by integrin V siRNA or scRNA. The representative immunoblots below the graph are of plasma membrane proteins and illustrate the effectiveness of the siRNA transfections for V and ß3. B) [14C]-Resveratrol binds to MCF-7 cell plasma membranes as well as to integrin monomers V and ß3. Two samples each of purified integrin Vß3 (Chemicon) and of plasma membrane proteins from MCF-7 cells were separated by 5% native PAGE. Proteins in one-half of the gel, with one membrane protein and one integrin sample, were transferred to nitrocellulose and subjected to Western blotting with Vß3 Ab (left panel). Immunoreactive proteins were detected by chemiluminescence. The remaining half of the gel, also containing one membrane protein and one purified integrin sample, was dried and exposed to Imaging Screen K (Bio-Rad) and studied by laser densitometry. Identification of monomers in immunoblots was by MW. Parallel studies of the radiolabeled and immunoreactive bands, from both purified integrin Vß3 and plasma membranes, reveal that 1) immunoreactive bands in plasma membranes and in purified integrin indicate V and ß3 proteins, and 2) both V and ß3 components of the integrin bind resveratrol. Additional studies were performed to determine the extent of displaceable binding. Purified integrin Vß3 was incubated with 10 µM [14C]-resveratrol (RV) in the absence or presence of 1 or 10 µM unlabeled RV for 30 min at room temperature. Samples were separated in 5% native gels, which were dried and analyzed by radioautography. Displacement by unlabeled resveratrol of [14C]-RV from the ß3 component of the integrin was observed at both stilbene concentrations, as shown in the graph (I.O.D., integrated optical density), with a 70% reduction in binding of radiolabeled RV to the ß3 component achieved with 10 µM unlabeled RV. Results shown are representative of three experiments.

To demonstrate direct interaction of resveratrol with integrin Vß3, studies of [¹⁴C]-resveratrol binding to plasma membranes or purified integrin were carried out. MCF-7 cell membrane proteins were solubilized with nonionic detergent, then incubated with [¹⁴C]-resveratrol for 30 min at 20°C and separated by nondenaturing PAGE. Purified integrin served as a positive control. Electrophoretic mobilities of the V and ß3 integrin monomers, shown by the immunoblots in Fig. 2B , were similar to those of the membrane protein bands from MCF-7 cells. Results of labeled resveratrol binding studies, performed in parallel with the immunoblots, indicate that labeled resveratrol was associated with protein bands in both cell membrane and purified integrin preparations, which are consistent with the V and ß3 components of the integrin.

In further studies, unlabeled resveratrol (1–10 µM) was added to purified integrin Vß3, which had previously been equilibrated with [¹⁴C]-resveratrol for 30 min, and was shown to bind to both V and ß3 (Fig. 2B , graph). Unlabeled resveratrol at 1 µM displaced a small amount of labeled resveratrol from the monomeric ß3 band, but the addition of 10 µM unlabeled resveratrol displaced 70% of the [¹⁴C]-resveratrol from the ß3 band. There was no effect of added resveratrol on binding of the stilbene by V. Thus, the binding of the stilbene to V was nonspecific in nature.

DISCUSSION

There are two members of the ß3 integrin family: IIbß3 and Vß3. Dysregulation of the ß3 integrins has been implicated in cancer pathogenesis. For example, tumor growth and associated angiogenesis, particularly that mediated by vascular endothelial growth factor, are enhanced in ß3-null mice (18) . Integrin ß3 overexpression, in contrast, suppresses tumor growth of a human glioma model in rats (19) . Together, these results suggest that promotion of integrin ß3 expression in cancer cells may be a therapeutic goal in the setting of cancer.

In the studies described here we show that integrin Vß3 satisfies the definition of a receptor in its binding of resveratrol. That is, dissociable ligand-binding and functional consequences of binding—transduction of the resveratrol signal into apoptosis—are demonstrated. The series of events initiated by resveratrol binding to integrin Vß3 in the plasma membrane is summarized in Fig. 3 and includes activation of the ERK1/2 pathway and consequent serine-15 phosphorylation of p53. Resulting p53-responsive gene transcription leads to cancer cell apoptosis. These actions of resveratrol have been well-documented (4 5 6 7) .

View larger version (36K): [in this window] [in a new window]   Figure 3. Proposed signaling pathway by which interaction of resveratrol with integrin Vß3 in the plasma membrane of cancer cells leads to cancer cell apoptosis. Resveratrol binds primarily to the ß3 monomer of the integrin, activating the ERK1/2 pathway with consequent phosphorylation of serine-15 of p53. We have previously shown that these steps are necessary for resveratrol-induced apoptosis to take place (4 , 5) . Nuclear phosphorylated p53 accumulates, leading to stimulation of p53-responsive gene transcription and apoptosis of breast cancer cells.

Commercially purified integrin Vß3 and integrin Vß3 in MCF-7 cell plasma membranes both bind resveratrol, and the binding of this ligand to monomeric ß3 is dissociable at a concentration of resveratrol which we have shown to be biologically active. From these studies and those with siRNA ß3, we propose that integrin binding to the ß3 monomer constitutes the principal site of stilbene interaction with the receptor. In addition, occlusion of the RGD binding site in the integrin extracellular domain blocks the cellular actions of resveratrol which we have previously described in a variety of cancer cell lines (4 , 5) including ERK1/2 pathway activation and serine phosphorylation of p53, leading to cancer cell apoptosis. The effectiveness of an RGD peptide, but not a control RGE peptide, as an inhibitor of resveratrol binding to the integrin suggests that the binding site for the stilbene on the receptor protein is at or near the RGD recognition site that is important to its interactions with extracellular matrix proteins. However, it is possible that the binding of RGD peptide by the integrin leads to allosteric changes in the protein that affect a resveratrol binding site elsewhere on the heterodimer.

In contrast to the studies reported here of breast cancer cells grown on culture plates, Tsan et al. have described resveratrol treatment of monocytic leukemia cells, which grow well in suspension (20) . In those studies, resveratrol effectively induced apoptosis at a concentration (12 µM) comparable to the concentrations used in the present study.

Appreciation that integrin Vß3 bears a receptor site for resveratrol suggests a role for the dimer as a screening tool for activity of resveratrol analogues (21) , and perhaps for estimating in vitro or in vivo responsiveness of tumor cells to the stilbene. The RGD domain of the integrin may also be a target for development of nonstilbene, small molecule pharmaceuticals with potential for induction of apoptosis in tumor cells. Translating resveratrol from an interesting naturally occurring substance into a specific ligand will facilitate more critical studies of its mechanisms of action.

ACKNOWLEDGMENTS

This work was supported in part by funding from the Office of Research Development, Medical Research Service, Department of Veterans Affairs (to H.-Y. L. and P.J.D.) and by support from the Charitable Leadership Foundation, the Candace King Weir Foundation, and the Beltrone Foundation. The authors declare that they have no competing financial interests.

Received for publication February 15, 2006. Accepted for publication March 31, 2006.

REFERENCES

1. Aggarwal, B. B., Bhardwaj, A., Aggarwal, R. S., Seeram, N. P., Shishodia, S., Takada, Y. (2004) Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 24,2783-2840[Medline]
2. Li, Y., Cao, Z., Zhu, H. (2006) Upregulation of endogenous antioxidants and phase 2 enzymes by the red wine polyphenol, resveratrol in cultured aortic smooth muscle cells leads to cytoprotection against oxidative and electrophilic stress. Pharmacol Res. 53,6-15[CrossRef][Medline]
3. Gao, Z. B., Hu, G. Y. (2005) Trans-resveratrol, a red wine ingredient, inhibits voltage-activated potassium currents in rat hippocampal neurons. Brain Res. 1056,68-75[CrossRef][Medline]
4. Zhang, S., Cao, H. J., Davis, F. B., Tang, H. Y., Davis, P. J., Lin, H. Y. (2004) Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells. Br. J. Cancer. 91,178-185[CrossRef][Medline]
5. Shih, A., Zhang, S., Cao, H. J., Boswell, S., Wu, Y. H., Tang, H. Y., Lennartz, M. R., Davis, F. B., Davis, P. J., Lin, H. Y. (2004) Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protein kinase C-alpha. Mol. Cancer Ther. 3,1355-1364[Abstract/Free Full Text]
6. She, Q. B., Huang, C., Zhang, Y., Dong, Z. (2002) Involvement of c-jun NH(2)-terminal kinases in resveratrol-induced activation of p53 and apoptosis. Mol. Carcinog. 33,244-250[CrossRef][Medline]
7. Signorelli, P., Ghidoni, R. (2005) Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J. Nutr. Biochem. 16,449-466[CrossRef][Medline]
8. Bhat, K. P., Pezzuto, J. M. (2001) Resveratrol exhibits cytostatic and antiestrogenic properties with human endometrial adenocarcinoma (Ishikawa) cells. Cancer Res. 61,6137-6144[Abstract/Free Full Text]
9. Hattangadi, D. K., DeMasters, G. A., Walker, T. D., Jones, K. R., Di, X., Newsham, I. F., Gewirtz, D. A. (2004) Influence of p53 and caspase 3 activity on cell death and senescence in response to methotrexate in the breast tumor cell. Biochem. Pharmacol. 68,1699-1708[CrossRef][Medline]
10. Plow, E. F., Haas, T. A., Zhang, L., Loftus, J., Smith, J. W. (2000) Ligand binding to integrins. J. Biol. Chem. 275,21785-21788[Free Full Text]
11. Bergh, J. J., Lin, H. Y., Lansing, L., Mohamed, S. N., Davis, F. B., Mousa, S., Davis, P. J. (2005) Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146,2864-2871[Abstract/Free Full Text]
12. Belvisi, L., Riccioni, T., Marcellini, M., Vesci, L., Chiarucci, I., Efrati, D., Potenza, D., Scolastico, C., Manzoni, L., Lombardo, K., Stasi, M. A., Orlandi, A., Ciucci, A., Nico, B., Ribatti, D., Giannini, G., Presta, M., Carminati, P., Pisano, C. (2005) Biological and molecular properties of a new alpha(v)beta3/alpha(v)beta5 integrin antagonist. Mol. Cancer Ther. 4,1670-1680[Abstract/Free Full Text]
13. Lin, H. Y., Shih, A., Davis, F. B., Tang, H. Y., Martino, L. J., Bennett, J. A., Davis, P. J. (2002) Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. J. Urol. 168,748-755[CrossRef][Medline]
14. Tang, H. Y., Lin, H. Y., Zhang, S., Davis, F. B., Davis, P. J. (2004) Thyroid hormone causes mitogen-activated protein kinase-dependent phosphorylation of the nuclear estrogen receptor. Endocrinology 145,3265-3272[Abstract/Free Full Text]
15. Lin, H. Y., Davis, F. B., Gordinier, J. K., Martino, L. J., Davis, P. J. (1999) Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. Am. J. Physiol. 276,C1014-C1024
16. Castro, M. R., Bergert, E. R., Beito, T. G., McIver, B., Goellner, J. R., Morris, J. C. (1999) Development of monoclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells. J. Clin. Endocrinol. Metab. 84,2957-2962[Abstract/Free Full Text]
17. Vitrac, X., Krisa, S., Decendit, A., Vercauteren, J., Nuhrich, A., Monti, J. P., Deffieux, G., Merillon, J. M. (2002) Carbon-14 biolabelling of wine polyphenols in Vitis vinifera cell suspension cultures. J. Biotechnol. 95,49-56[CrossRef][Medline]
18. Reynolds, A. R., Reynolds, L. E., Nagel, T. E., Lively, J. C., Robinson, S. D., Hicklin, D. J., Bodary, S. C., Hodivala-Dilke, K. M. (2004) Elevated Flk1 (vascular endothelial growth factor receptor 2) signaling mediates enhanced angiogenesis in beta3-integrin-deficient mice. Cancer Res. 64,8643-8650[Abstract/Free Full Text]
19. Kanamori, M., Vanden Berg, S. R., Bergers, G., Berger, M. S., Pieper, R. O. (2004) Integrin beta3 overexpression suppresses tumor growth in a human model of gliomagenesis: implications for the role of beta3 overexpression in glioblastoma multiforme. Cancer Res. 64,2751-2758[Abstract/Free Full Text]
20. Tsan, M. F., White, J. E., Maheshwari, J. G., Bremner, T. A., Sacco, J. (2000) Resveratrol induces Fas signalling-independent apoptosis in THP-1 human monocytic leukaemia cells. Br. J. Haematol. 109,405-412[CrossRef][Medline]
21. Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L. L., Scherer, B., Sinclair, D. A. (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425,191-196[CrossRef][Medline]

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