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 Madak-Erdogan, Z. Articles by Katzenellenbogen, B. S. Search for Related Content PubMed PubMed Citation Articles by Madak-Erdogan, Z. Articles by Katzenellenbogen, B. S.

Nuclear and Extranuclear Pathway Inputs in the Regulation of Global Gene Expression by Estrogen Receptors

Department of Cell and Developmental Biology (Z.M.-E., B.S.K.), Department of Chemistry (K.J.K., S.H.K., J.A.K.), and Department of Molecular and Integrative Physiology (K.J.K., B.S.K.), University of Illinois, Urbana, Illinois 61801; and Women’s Health and Musculoskeletal Biology (B.K.), Wyeth Research, Collegeville, Pennsylvania 19426

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.

Whereas estrogens exert their effects by binding to nuclear estrogen receptors (ERs) and directly altering target gene transcription, they can also initiate extranuclear signaling through activation of kinase cascades. We have investigated the impact of estrogen-mediated extranuclear-initiated pathways on global gene expression by using estrogen-dendrimer conjugates (EDCs), which because of their charge and size remain outside the nucleus and can only initiate extranuclear signaling. Genome-wide cDNA microarray analysis of MCF-7 breast cancer cells identified a subset of 17β-estradiol (E2)-regulated genes (25%) as EDC responsive. The EDC and E2-elicited increases in gene expression were due to increases in gene transcription, as observed in nuclear run-on assays and RNA polymerase II recruitment and phosphorylation. Treatment with antiestrogen or ER knockdown using small interfering RNA abolished EDC-mediated gene stimulation, whereas GPR30 knockdown or treatment with a GPR30-selective ligand was without effect, indicating ER as the mediator of these gene regulations. Inhibitors of MAPK kinase and c-Src suppressed both E2 and EDC stimulated gene expression. Of note, in chromatin immunoprecipitation assays, EDC was unable to recruit ER to estrogen-responsive regions of regulated genes, whereas ER recruitment by E2 was very effective. These findings suggest that other transcription factors or kinases that are downstream effectors of EDC-initiated extranuclear signaling cascades are recruited to regulatory regions of EDC-responsive genes in order to elicit gene stimulation. This study thus highlights the importance of inputs from both nuclear and extranuclear ER signaling pathways in regulating patterns of gene expression in breast cancer cells.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

This article has been cited by other articles:

				K. Hashimoto, E. Ishida, S. Matsumoto, S. Okada, M. Yamada, T. Satoh, T. Monden, and M. Mori Carbohydrate Response Element Binding Protein Gene Expression Is Positively Regulated by Thyroid Hormone Endocrinology, July 1, 2009; 150(7): 3417 - 3424. [Abstract] [Full Text] [PDF]

				E. R. Levin G Protein-Coupled Receptor 30: Estrogen Receptor or Collaborator? Endocrinology, April 1, 2009; 150(4): 1563 - 1565. [Full Text] [PDF]

				F. Stossi, Z. Madak-Erdogan, and B. S. Katzenellenbogen Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1 Mol. Cell. Biol., April 1, 2009; 29(7): 1749 - 1759. [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]

				E. R. Levin Rapid signaling by steroid receptors Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2008; 295(5): R1425 - R1430. [Abstract] [Full Text] [PDF]