This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Harrington, W. R. Articles by Katzenellenbogen, B. S. Search for Related Content PubMed PubMed Citation Articles by Harrington, W. R. Articles by Katzenellenbogen, B. S.

Estrogen Dendrimer Conjugates that Preferentially Activate Extranuclear, Nongenomic Versus Genomic Pathways of Estrogen Action

Department of Molecular and Integrative Physiology (W.R.H., B.S.K.), Department of Chemistry (S.H.K., J.A.K.), and Department of Cell and Developmental Biology (C.C.F., Z.M.-E., B.S.K.), University of Illinois, Urbana, Illinois 61801; and Department of Medicine (R.S.), Breast Center, Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Benita S. Katzenellenbogen, University of Illinois, Department of Molecular and Integrative Physiology, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801-3704. E-mail: katzenel{at}uiuc.edu.

Estrogenic hormones are classically thought to exert their effects by binding to nuclear estrogen receptors and altering target gene transcription, but estrogens can also have nongenomic effects through rapid activation of membrane-initiated kinase cascades. The development of ligands that selectively activate only the nongenomic pathways would provide useful tools to investigate the significance of these pathways. We have prepared large, abiotic, nondegradable poly(amido)amine dendrimer macromolecules that are conjugated to multiple estrogen molecules through chemically robust linkages. Because of their charge and size, these estrogen-dendrimer conjugates (EDCs) remain outside the nucleus. They stimulate ERK, Shc, and Src phosphorylation in MCF-7 breast cancer cells at low concentrations, yet they are very ineffective in stimulating transcription of endogenous estrogen target genes, being approximately 10,000-fold less potent than estradiol in genomic actions. In contrast to estradiol, EDC was not effective in stimulating breast cancer cell proliferation. Because these EDC ligands activate nongenomic activity at concentrations at which they do not alter the transcription of estrogen target genes, they should be useful in studying extranuclear initiated pathways of estrogen action in a variety of target cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  PR

Ligands:   17β-Estradiol

This article has been cited by other articles:

				Q.-G. Zhang, L. Raz, R. Wang, D. Han, L. De Sevilla, F. Yang, R. K. Vadlamudi, and D. W. Brann Estrogen Attenuates Ischemic Oxidative Damage via an Estrogen Receptor {alpha}-Mediated Inhibition of NADPH Oxidase Activation J. Neurosci., November 4, 2009; 29(44): 13823 - 13836. [Abstract] [Full Text] [PDF]

				S. Liu, C. Le May, W. P.S. Wong, R. D. Ward, D. J. Clegg, M. Marcelli, K. S. Korach, and F. Mauvais-Jarvis Importance of Extranuclear Estrogen Receptor-{alpha} and Membrane G Protein-Coupled Estrogen Receptor in Pancreatic Islet Survival Diabetes, October 1, 2009; 58(10): 2292 - 2302. [Abstract] [Full Text] [PDF]

				A. M. Fowler, R. J. Santen, and D. C. Allred "Dwarf" Estrogen Receptor in Breast Cancer and Resistance to Tamoxifen J. Clin. Oncol., July 20, 2009; 27(21): 3413 - 3415. [Full Text] [PDF]

				B. C. Lin, M. Suzawa, R. D. Blind, S. C. Tobias, S. E. Bulun, T. S. Scanlan, and H. A. Ingraham Stimulating the GPR30 Estrogen Receptor with a Novel Tamoxifen Analogue Activates SF-1 and Promotes Endometrial Cell Proliferation Cancer Res., July 1, 2009; 69(13): 5415 - 5423. [Abstract] [Full Text] [PDF]

				E. N. Nierth-Simpson, M. M. Martin, T.-C. Chiang, L. I. Melnik, L. V. Rhodes, S. E. Muir, M. E. Burow, and J. A. McLachlan Human Uterine Smooth Muscle and Leiomyoma Cells Differ in Their Rapid 17{beta}-Estradiol Signaling: Implications for Proliferation Endocrinology, May 1, 2009; 150(5): 2436 - 2445. [Abstract] [Full Text] [PDF]

				Z. Wang, G. T. Wijewickrama, K.-w. Peng, B. M. Dietz, L. Yuan, R. B. van Breemen, J. L. Bolton, and G. R. J. Thatcher Estrogen Receptor {alpha} Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus J. Biol. Chem., March 27, 2009; 284(13): 8633 - 8642. [Abstract] [Full Text] [PDF]

				S. D. Noel, K. L. Keen, D. I. Baumann, E. J. Filardo, and E. Terasawa Involvement of G Protein-Coupled Receptor 30 (GPR30) in Rapid Action of Estrogen in Primate LHRH Neurons Mol. Endocrinol., March 1, 2009; 23(3): 349 - 359. [Abstract] [Full Text] [PDF]

				S. P. Yun, M. Y. Lee, J. M. Ryu, C. H. Song, and H. J. Han Role of HIF-1{alpha} and VEGF in human mesenchymal stem cell proliferation by 17{beta}-estradiol: involvement of PKC, PI3K/Akt, and MAPKs Am J Physiol Cell Physiol, February 1, 2009; 296(2): C317 - C326. [Abstract] [Full Text] [PDF]

				Z. Madak-Erdogan, K. J. Kieser, S. H. Kim, B. Komm, J. A. Katzenellenbogen, and B. S. Katzenellenbogen Nuclear and Extranuclear Pathway Inputs in the Regulation of Global Gene Expression by Estrogen Receptors Mol. Endocrinol., September 1, 2008; 22(9): 2116 - 2127. [Abstract] [Full Text] [PDF]

				H. Abe, K. L. Keen, and E. Terasawa Rapid Action of Estrogens on Intracellular Calcium Oscillations in Primate Luteinizing Hormone-Releasing Hormone-1 Neurons Endocrinology, March 1, 2008; 149(3): 1155 - 1162. [Abstract] [Full Text] [PDF]

				S. R. Hammes and E. R. Levin Extranuclear Steroid Receptors: Nature and Actions Endocr. Rev., December 1, 2007; 28(7): 726 - 741. [Abstract] [Full Text] [PDF]

				M. Chang, K.-w. Peng, I. Kastrati, C. R. Overk, Z.-H. Qin, P. Yao, J. L. Bolton, and G. R. J. Thatcher Activation of Estrogen Receptor-Mediated Gene Transcription by the Equine Estrogen Metabolite, 4-Methoxyequilenin, in Human Breast Cancer Cells Endocrinology, October 1, 2007; 148(10): 4793 - 4802. [Abstract] [Full Text] [PDF]

				N. Heldring, A. Pike, S. Andersson, J. Matthews, G. Cheng, J. Hartman, M. Tujague, A. Strom, E. Treuter, M. Warner, et al. Estrogen Receptors: How Do They Signal and What Are Their Targets Physiol Rev, July 1, 2007; 87(3): 905 - 931. [Abstract] [Full Text] [PDF]

				C. M. Silva and M. A. Shupnik Integration of Steroid and Growth Factor Pathways in Breast Cancer: Focus on Signal Transducers and Activators of Transcription and Their Potential Role in Resistance Mol. Endocrinol., July 1, 2007; 21(7): 1499 - 1512. [Abstract] [Full Text] [PDF]

				S. Kousteni, M. Almeida, L. Han, T. Bellido, R. L. Jilka, and S. C. Manolagas Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor Mol. Cell. Biol., February 15, 2007; 27(4): 1516 - 1530. [Abstract] [Full Text] [PDF]

				S. Tang, Z. Zhang, S. L. Tan, M.-H. E. Tang, A. P. Kumar, S. K. Ramadoss, and V. B. Bajic KBERG: KnowledgeBase for Estrogen Responsive Genes Nucleic Acids Res., January 12, 2007; 35(suppl_1): D732 - D736. [Abstract] [Full Text] [PDF]

				V. S. Likhite, F. Stossi, K. Kim, B. S. Katzenellenbogen, and J. A. Katzenellenbogen Kinase-Specific Phosphorylation of the Estrogen Receptor Changes Receptor Interactions with Ligand, Deoxyribonucleic Acid, and Coregulators Associated with Alterations in Estrogen and Tamoxifen Activity Mol. Endocrinol., December 1, 2006; 20(12): 3120 - 3132. [Abstract] [Full Text] [PDF]

				R. X.-D. Song and R. J. Santen Membrane Initiated Estrogen Signaling in Breast Cancer Biol Reprod, July 1, 2006; 75(1): 9 - 16. [Abstract] [Full Text] [PDF]