The Estrogen Receptor ␤-isoform (er␤) of the Human Estrogen Receptor Modulates Er␣ Transcriptional Activity and Is a Key Regulator of the Cellular Response to Estrogens and Antiestrogens*

The human estrogen receptor alpha (ERalpha) and the recently identified ERbeta share a high degree of amino acid homology; however, there are significant differences in regions of these receptors that would be expected to influence transcriptional activity. Consequently, we compared the mechanism(s) by which these receptors regulate target gene transcription, and evaluated the cellular consequences of coexpression of both ER subtypes. Previously, it has been determined that ERalpha contains two distinct activation domains, ERalpha-AF-1 and ERalpha-AF-2, whose transcriptional activity is influenced by cell and promoter context. We determined that ERbeta, like ERalpha, contains a functional AF-2, however, the ERbeta-AF-2 domain functions independently within the receptor. Of additional significance was the finding that ERbeta does not contain a strong AF-1 within its amino-terminus but, rather, contains a repressor domain that when removed, increases the overall transcriptional activity of the receptor. The importance of these findings was revealed when it was determined that ERbeta functions as a transdominant inhibitor of ERalpha transcriptional activity at subsaturating hormone levels and that ERbeta decreases overall cellular sensitivity to estradiol. Additionally, the partial agonist activity of tamoxifen manifest through ERalpha in some contexts was completely abolished upon coexpression of ERbeta. In probing the mechanisms underlying ERbeta-mediated repression of ERalpha transcriptional activity we have determined that 1) ERalpha and ERbeta can form heterodimers within target cells; and 2) ERbeta interacts with target gene promoters in a ligand-independent manner. Cumulatively, these data indicate that one role of ERbeta is to modulate ERalpha transcriptional activity, and thus the relative expression level of the two isoforms will be a key determinant of cellular responses to agonists and antagonists.

[1]  V. Giguère,et al.  Ligand-independent recruitment of SRC-1 to estrogen receptor beta through phosphorylation of activation function AF-1. , 1999, Molecular cell.

[2]  John H. White,et al.  Different Classes of Coactivators Recognize Distinct but Overlapping Binding Sites on the Estrogen Receptor Ligand Binding Domain* , 1998, The Journal of Biological Chemistry.

[3]  J. Lehmann,et al.  Cloning and Characterization of Human Estrogen Receptor β Isoforms , 1998 .

[4]  B. McEwen,et al.  Differential colocalization of estrogen receptor beta (ERbeta) with oxytocin and vasopressin in the paraventricular and supraoptic nuclei of the female rat brain: an immunocytochemical study. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  P. Giangrande,et al.  Mapping and Characterization of the Functional Domains Responsible for the Differential Activity of the A and B Isoforms of the Human Progesterone Receptor* , 1997, The Journal of Biological Chemistry.

[6]  K. Korach,et al.  Tissue Distribution and Quantitative Analysis of Estrogen Receptor-α (ERα) and Estrogen Receptor-β (ERβ) Messenger Ribonucleic Acid in the Wild-Type and ERα-Knockout Mouse. , 1997, Endocrinology.

[7]  T. Willson,et al.  Dissection of the molecular mechanism of action of GW5638, a novel estrogen receptor ligand, provides insights into the role of estrogen receptor in bone. , 1997, Endocrinology.

[8]  S. Cowley,et al.  Estrogen Receptors α and β Form Heterodimers on DNA* , 1997, The Journal of Biological Chemistry.

[9]  H. Dotzlaq.  Expression of Estrogen Receptor- in Human Breast Tumors , 1997 .

[10]  Helmut Dotzlaw,et al.  Expression of estrogen receptor-beta in human breast tumors. , 1997, The Journal of clinical endocrinology and metabolism.

[11]  K. Grandien,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors � and � , 2022 .

[12]  N. Copeland,et al.  Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. , 1997, Molecular endocrinology.

[13]  D. McDonnell,et al.  Identification of the sequences within the human complement 3 promoter required for estrogen responsiveness provides insight into the mechanism of tamoxifen mixed agonist activity. , 1996, Molecular endocrinology.

[14]  B. Komm,et al.  The distribution of estrogen receptor-β mRNA in the rat hypothalamus , 1996, Steroids.

[15]  K. Korach,et al.  Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Horwitz,et al.  Nuclear receptor coactivators and corepressors. , 1996, Molecular endocrinology.

[17]  B. Katzenellenbogen,et al.  Different Regions in Activation Function-1 of the Human Estrogen Receptor Required for Antiestrogen- and Estradiol-dependent Transcription Activation* , 1996, The Journal of Biological Chemistry.

[18]  J. Gustafsson,et al.  Cloning of a novel receptor expressed in rat prostate and ovary. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Stallcup,et al.  GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Cidlowski,et al.  The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. , 1996, The Journal of biological chemistry.

[21]  B. O’Malley,et al.  Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily , 1995, Science.

[22]  P. Deininger,et al.  Identification of a New Subclass of Alu DNA Repeats Which Can Function as Estrogen Receptor-dependent Transcriptional Enhancers (*) , 1995, The Journal of Biological Chemistry.

[23]  M. Imhof,et al.  Cellular Mechanisms Which Distinguish between Hormone‐ and Antihormone‐Activated Estrogen Receptor , 1995, Annals of the New York Academy of Sciences.

[24]  Andrew J. Bannister,et al.  An inhibitor domain in c‐Fos regulates activation domains containing the HOB1 motif. , 1995, The EMBO journal.

[25]  B. O’Malley,et al.  Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. , 1993, Molecular endocrinology.

[26]  K. Korach,et al.  Peptide growth factors elicit estrogen receptor-dependent transcriptional activation of an estrogen-responsive element. , 1993, Molecular endocrinology.

[27]  B. Katzenellenbogen,et al.  Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. , 1993, Molecular endocrinology.

[28]  P. Chambon,et al.  Role of the two activating domains of the oestrogen receptor in the cell‐type and promoter‐context dependent agonistic activity of the anti‐oestrogen 4‐hydroxytamoxifen. , 1990, The EMBO journal.

[29]  W. Schaffner,et al.  Identification of a novel lymphoid specific octamer binding protein (OTF‐2B) by proteolytic clipping bandshift assay (PCBA). , 1988, The EMBO journal.

[30]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[31]  J. Gustafsson,et al.  Mouse Estrogen Receptor (cid:98) Forms Estrogen Response Element-Binding Heterodimers with Estrogen Receptor (cid:97) , 1997 .

[32]  G. Jenster,et al.  Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action. , 1997, Recent progress in hormone research.

[33]  J. Polman,et al.  ER beta: identification and characterization of a novel human estrogen receptor. , 1996, FEBS letters.

[34]  M. Tzukerman,et al.  Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. , 1994, Molecular endocrinology.

[35]  B. O’Malley,et al.  Molecular mechanisms of action of steroid/thyroid receptor superfamily members. , 1994, Annual review of biochemistry.