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Molecular Endocrinology, Vol 8, 21-30, Copyright © 1994 by Endocrine Society

ARTICLES

Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions

MT Tzukerman, A Esty, D Santiso-Mere, P Danielian, MG Parker, RB Stein, JW Pike and DP McDonnell
Department of Molecular Biology, Ligand Pharmaceuticals, Inc., San Diego, California 92121.

We have used a series of human estrogen receptor (ER) mutants to evaluate the cell- and promoter-specific transcriptional activities of the TAF1 and TAF2 transactivation regions within the human ER. We show that the manifestation of TAF1 or TAF2 function depends strongly upon promoter context; on certain promoters, both the TAF1 and TAF2 activators are required for wild-type transcriptional activity, whereas on other promoters, the TAF1 and TAF2 activators function independently. Using these constructs, we show that the antagonist activity of the triphenylethylene-derived antiestrogens, e.g. tamoxifen, arises from their intrinsic inability to activate ER TAF2 function. However, on certain promoters, these antiestrogens efficiently activate gene transcription through ER. Consistent with this observation, the TAF2 function of the ER is not required on all promoters. In these TAF2-independent promoter contexts, TAF2 function may be provided by a separate transcription factor bound to the promoter. These data suggest that 1) TAF1 may be the major transcriptional activator of the ER; and 2) TAF2 functions as a transcriptional facilitator. On promoters where TAF2 function is provided independently of the ER, the TAF1 function of the ER can function independently of TAF2 activity, allowing triphenylethylene- derived antiestrogens to demonstrate partial agonist activity. These observations provide a possible molecular explanation for the tissue- specific partial agonist properties of tamoxifen and related triphenylethylene antiestrogens observed in vivo.


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K. Kim, N. Thu, B. Saville, and S. Safe
Domains of Estrogen Receptor {alpha} (ER{alpha}) Required for ER{alpha}/Sp1-Mediated Activation of GC-Rich Promoters by Estrogens and Antiestrogens in Breast Cancer Cells
Mol. Endocrinol., May 1, 2003; 17(5): 804 - 817.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
K. M. Coleman, M. Dutertre, A. El-Gharbawy, B. G. Rowan, N. L. Weigel, and C. L. Smith
Mechanistic Differences in the Activation of Estrogen Receptor-alpha (ERalpha )- and ERbeta -dependent Gene Expression by cAMP Signaling Pathway(s)
J. Biol. Chem., April 4, 2003; 278(15): 12834 - 12845.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
X. Hu, L. Cherbas, and P. Cherbas
Transcription Activation by the Ecdysone Receptor (EcR/USP): Identification of Activation Functions
Mol. Endocrinol., April 1, 2003; 17(4): 716 - 731.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
K. D. Houston, J. A. Copland, R. R. Broaddus, M. M. Gottardis, S. M. Fischer, and C. L. Walker
Inhibition of Proliferation and Estrogen Receptor Signaling by Peroxisome Proliferator-activated Receptor {gamma} Ligands in Uterine Leiomyoma
Cancer Res., March 15, 2003; 63(6): 1221 - 1227.
[Abstract] [Full Text] [PDF]

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 DevelopmentHome page
L. Cherbas, X. Hu, I. Zhimulev, E. Belyaeva, and P. Cherbas
EcR isoforms in Drosophila: testing tissue-specific requirements by targeted blockade and rescue
Development, March 2, 2003; 130(2): 271 - 284.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. T. Pearce, H. Liu, and V. C. Jordan
Modulation of Estrogen Receptor alpha Function and Stability by Tamoxifen and a Critical Amino Acid (Asp-538) in Helix 12
J. Biol. Chem., February 21, 2003; 278(9): 7630 - 7638.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
R. R. Rajendran, A. C. Nye, J. Frasor, R. D. Balsara, P. G. V. Martini, and B. S. Katzenellenbogen
Regulation of Nuclear Receptor Transcriptional Activity by a Novel DEAD Box RNA Helicase (DP97)
J. Biol. Chem., February 7, 2003; 278(7): 4628 - 4638.
[Abstract] [Full Text] [PDF]

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 Mol Cancer ResHome page
L. C. Hodges, J. D. Cook, E. K. Lobenhofer, L. Li, L. Bennett, P. R. Bushel, C. M. Aldaz, C. A. Afshari, and C. L. Walker
Tamoxifen Functions As a Molecular Agonist Inducing Cell Cycle-Associated Genes in Breast Cancer Cells
Mol. Cancer Res., February 1, 2003; 1(4): 300 - 311.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. M. Hall and K. S. Korach
Analysis of the Molecular Mechanisms of Human Estrogen Receptors alpha and beta Reveals Differential Specificity in Target Promoter Regulation by Xenoestrogens
J. Biol. Chem., November 8, 2002; 277(46): 44455 - 44461.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
C. Qi, J. Chang, Y. Zhu, A. V. Yeldandi, S. M. Rao, and Y.-J. Zhu
Identification of Protein Arginine Methyltransferase 2 as a Coactivator for Estrogen Receptor alpha
J. Biol. Chem., August 2, 2002; 277(32): 28624 - 28630.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
G. Sathya, M. S. Jansen, S. C. Nagel, C. E. Cook, and D. P. MCDonnell
Identification and Characterization of Novel Estrogen Receptor-{beta}-Sparing Antiprogestins
Endocrinology, August 1, 2002; 143(8): 3071 - 3082.
[Abstract] [Full Text] [PDF]

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 Toxicol SciHome page
G. D. Charles, C. Gennings, T. R. Zacharewski, B. B. Gollapudi, and E. W. Carney
An Approach for Assessing Estrogen Receptor-Mediated Interactions in Mixtures of Three Chemicals: A Pilot Study
Toxicol. Sci., August 1, 2002; 68(2): 349 - 360.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
P. Yi, S. Bhagat, R. Hilf, R. A. Bambara, and M. Muyan
Differences in the Abilities of Estrogen Receptors to Integrate Activation Functions Are Critical for Subtype-Specific Transcriptional Responses
Mol. Endocrinol., August 1, 2002; 16(8): 1810 - 1827.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Cui, T. S. Heard, J. Yu, J.-L. Lo, L. Huang, Y. Li, J. M. Schaeffer, and S. D. Wright
The Amino Acid Residues Asparagine 354 and Isoleucine 372 of Human Farnesoid X Receptor Confer the Receptor with High Sensitivity to Chenodeoxycholate
J. Biol. Chem., July 12, 2002; 277(29): 25963 - 25969.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
J. Chen, S. Kaul, and S. S. Simons Jr.
Structure/Activity Elements of the Multifunctional Protein, GMEB-1. CHARACTERIZATION OF DOMAINS RELEVANT FOR THE MODULATION OF GLUCOCORTICOID RECEPTOR TRANSACTIVATION PROPERTIES
J. Biol. Chem., June 7, 2002; 277(24): 22053 - 22062.
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 ScienceHome page
D. P. McDonnell and J. D. Norris
Connections and Regulation of the Human Estrogen Receptor
Science, May 31, 2002; 296(5573): 1642 - 1644.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Kressler, S. N. Schreiber, D. Knutti, and A. Kralli
The PGC-1-related Protein PERC Is a Selective Coactivator of Estrogen Receptor alpha
J. Biol. Chem., April 12, 2002; 277(16): 13918 - 13925.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. Kaul, J. A. Blackford Jr., S. Cho, and S. S. Simons Jr.
Ubc9 Is a Novel Modulator of the Induction Properties of Glucocorticoid Receptors
J. Biol. Chem., April 5, 2002; 277(15): 12541 - 12549.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
C.-Y. Chang and D. P. McDonnell
Evaluation of Ligand-Dependent Changes in AR Structure Using Peptide Probes
Mol. Endocrinol., April 1, 2002; 16(4): 647 - 660.
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 Mol. Endocrinol.Home page
P. Yi, M. D. Driscoll, J. Huang, S. Bhagat, R. Hilf, R. A. Bambara, and M. Muyan
The Effects of Estrogen-Responsive Element- and Ligand-Induced Structural Changes on the Recruitment of Cofactors and Transcriptional Responses by ER{alpha} and ER{beta}
Mol. Endocrinol., April 1, 2002; 16(4): 674 - 693.
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 ScienceHome page
Y. Shang and M. Brown
Molecular Determinants for the Tissue Specificity of SERMs
Science, March 29, 2002; 295(5564): 2465 - 2468.
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 Mol. Endocrinol.Home page
J. D. Norris, D. Fan, A. Sherk, and D. P. McDonnell
A Negative Coregulator for the Human ER
Mol. Endocrinol., March 1, 2002; 16(3): 459 - 468.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
J. M. Hall, D. P. McDonnell, and K. S. Korach
Allosteric Regulation of Estrogen Receptor Structure, Function, and Coactivator Recruitment by Different Estrogen Response Elements
Mol. Endocrinol., March 1, 2002; 16(3): 469 - 486.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
R. V. Weatherman, C.-Y. Chang, N. J. Clegg, D. C. Carroll, R. N. Day, J. D. Baxter, D. P. McDonnell, T. S. Scanlan, and F. Schaufele
Ligand-Selective Interactions of ER Detected in Living Cells by Fluorescence Resonance Energy Transfer
Mol. Endocrinol., March 1, 2002; 16(3): 487 - 496.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
C. Pendaries, B. Darblade, P. Rochaix, A. Krust, P. Chambon, K. S. Korach, F. Bayard, and J.-F. Arnal
The AF-1 activation-function of ERalpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice
PNAS, February 19, 2002; 99(4): 2205 - 2210.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
I. T. R. Cavarretta, R. Mukopadhyay, D. M. Lonard, L. M. Cowsert, C. F. Bennett, B. W. O'Malley, and C. L. Smith
Reduction of Coactivator Expression by Antisense Oligodeoxynucleotides Inhibits ER{alpha} Transcriptional Activity and MCF-7 Proliferation
Mol. Endocrinol., February 1, 2002; 16(2): 253 - 270.
[Abstract] [Full Text] [PDF]

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 Recent Prog Horm ResHome page
D. P. McDonnell, C. E. Connor, A. Wijayaratne, C.-y. Chang, and J. D. Norris
Definition of the Molecular and Cellular Mechanisms Underlying the Tissue-selective Agonist/Antagonist Activities of Selective Estrogen Receptor Modulators
Recent Prog. Horm. Res., January 1, 2002; 57(1): 295 - 316.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
Z.-Q. Ma, Z. Liu, E. S. W. Ngan, and S. Y. Tsai
Cdc25B Functions as a Novel Coactivator for the Steroid Receptors
Mol. Cell. Biol., December 1, 2001; 21(23): 8056 - 8067.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
S. Denger, G. Reid, M. Kos, G. Flouriot, D. Parsch, H. Brand, K. S. Korach, V. Sonntag-Buck, and F. Gannon
ER{alpha} Gene Expression in Human Primary Osteoblasts: Evidence for the Expression of Two Receptor Proteins
Mol. Endocrinol., December 1, 2001; 15(12): 2064 - 2077.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
A. Warnmark, A. Wikstrom, A. P. H. Wright, J.-A. Gustafsson, and T. Hard
The N-terminal Regions of Estrogen Receptor alpha and beta Are Unstructured in Vitro and Show Different TBP Binding Properties
J. Biol. Chem., November 30, 2001; 276(49): 45939 - 45944.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
R. Metivier, G. Penot, G. Flouriot, and F. Pakdel
Synergism Between ER{alpha} Transactivation Function 1 (AF-1) and AF-2 Mediated by Steroid Receptor Coactivator Protein-1: Requirement for the AF-1 {alpha}-Helical Core and for a Direct Interaction Between the N- and C-Terminal Domains
Mol. Endocrinol., November 1, 2001; 15(11): 1953 - 1970.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S. C. Nagel, J. L. Hagelbarger, and D. P. McDonnell
Development of an ER Action Indicator Mouse for the Study of Estrogens, Selective ER Modulators (SERMs), and Xenobiotics
Endocrinology, November 1, 2001; 142(11): 4721 - 4728.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
K. P. L. Bhat, D. Lantvit, K. Christov, R. G. Mehta, R. C. Moon, and J. M. Pezzuto
Estrogenic and Antiestrogenic Properties of Resveratrol in Mammary Tumor Models
Cancer Res., October 1, 2001; 61(20): 7456 - 7463.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. Tiffoche, C. Vaillant, D. Schausi, and M.-L. Thieulant
Novel Intronic Promoter in the Rat ER{alpha} Gene Responsible for the Transient Transcription of a Variant Receptor
Endocrinology, September 1, 2001; 142(9): 4106 - 4119.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. A. Schreihofer, E. M. Resnick, V. Y. Lin, and M. A. Shupnik
Ligand-Independent Activation of Pituitary ER: Dependence on PKA-Stimulated Pathways
Endocrinology, August 1, 2001; 142(8): 3361 - 3368.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
C. Pasqualini, D. Guivarc'h, J.-V. Barnier, B. Guibert, J.-D. Vincent, and P. Vernier
Differential Subcellular Distribution and Transcriptional Activity of {{Sigma}}E3, {{Sigma}}E4, and {{Sigma}}E3-4 Isoforms of the Rat Estrogen Receptor-{{alpha}}
Mol. Endocrinol., June 1, 2001; 15(6): 894 - 908.
[Abstract] [Full Text] [PDF]


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