Interfering with the Dynamics of Estrogen Receptor-Regulated Transcription

  • S. A. Johnsen
  • S. Kangaspeska
  • G. Reid
  • F. Gannon
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2006/1)


In recent years, there has been a growing realization that a static two-dimensional model of gene activation by transcription factors is inadequate. Based on the work from a number of groups (Kang et al. 2002; Liu and Bagchi 2004; Metivier et al. 2003; Park et al. 2005; Reid et al. 2003; Shang et al. 2000; Sharma and Fondell 2002; Vaisanen et al. 2005), it is becoming clear that transcriptional regulation by nuclear receptors is a dynamic and cyclical process (Metivier et al. 2006). There are significant consequences that arise from this shift in understanding, from nuclear receptors as ligand activated factors that bind to a response element to activate expression of a target gene to a process where the receptor repeatedly binds in order to achieve transcription. New insights that arise from viewing the activation process as cyclical and the consequences of this for developing new strategies that modulate the activity of the estrogen receptor are outlined in this chapter.


Ubiquitin Ligase Proteasome Inhibitor Estrogen Response Element Proteasome Component Activate Target Gene Transcription 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Chavez-Blanco A, Segura-Pacheco B, Perez-Cardenas E et al. (2005) Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Mol Cancer 4:22PubMedCrossRefGoogle Scholar
  2. Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6:79–87PubMedCrossRefGoogle Scholar
  3. Duncan S (2001) Polycystic ovarian syndrome in women with epilepsy: a review. Epilepsia 42(Suppl 3):60–65PubMedCrossRefGoogle Scholar
  4. Flouriot G, Brand H, Denger S et al. (2000) Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J 19:4688–4700PubMedCrossRefGoogle Scholar
  5. Isojarvi JI, Laatikainen TJ, Pakarinen AJ et al. (1993) Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 329:1383–1388PubMedCrossRefGoogle Scholar
  6. Kang Z, Pirskanen A, Janne OA et al. (2002) Involvement of proteasome in the dynamic assembly of the androgen receptor transcription complex. J Biol Chem 277:48366–48371PubMedCrossRefGoogle Scholar
  7. Kramer OH, Zhu P, Ostendorff HP et al. (2003) The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 22:3411--3420PubMedCrossRefGoogle Scholar
  8. Liu XF, Bagchi MK (2004) Recruitment of distinct chromatin-modifying complexes by tamoxifen-complexed estrogen receptor at natural target gene promoters in vivo. J Biol Chem 279:15050–15058PubMedCrossRefGoogle Scholar
  9. Lonard DM, Nawaz Z, Smith CL et al. (2000) The 26S proteasome is required for estrogen receptor-alpha and coactivator turnover and for efficient estrogen receptor-alpha transactivation. Mol Cell 5:939–948PubMedCrossRefGoogle Scholar
  10. Metivier R, Penot G, Hubner MR et al. (2003) Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115:751–763PubMedCrossRefGoogle Scholar
  11. Metivier R, Penot G, Carmouche RP et al. (2004) Transcriptional complexes engaged by apo-estrogen receptor-alpha isoforms have divergent outcomes. EMBO J 23:3653–3666PubMedCrossRefGoogle Scholar
  12. Metivier R, Reid G, Gannon F (2006) Transcription in four dimensions: nuclear receptor-directed initiation of gene expression. EMBO Rep 7:161–167PubMedCrossRefGoogle Scholar
  13. Muratani M, Tansey WP (2003) How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol 4:192–201PubMedCrossRefGoogle Scholar
  14. Nawaz Z, Lonard DM, Dennis AP et al. (1999) Proteasome-dependent degradation of the human estrogen receptor. Proc Natl Acad Sci USA 96:1858–1862PubMedCrossRefGoogle Scholar
  15. Nirmala PB, Thampan RV (1995) Ubiquitination of the rat uterine estrogen receptor: dependence on estradiol. Biochem Biophys Res Commun 213:24–31PubMedCrossRefGoogle Scholar
  16. O'Donovan C, Kusumakar V, Graves GR et al. (2002) Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 63:322–330PubMedCrossRefGoogle Scholar
  17. Park KJ, Krishnan V, O'Malley BW et al. (2005) Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. Mol Cell 18:71–82PubMedCrossRefGoogle Scholar
  18. Preisler-Mashek MT, Solodin N, Stark BL et al. (2002) Ligand-specific regulation of proteasome-mediated proteolysis of estrogen receptor-alpha. Am J Physiol Endocrinol Metab 282:E891–E898PubMedGoogle Scholar
  19. Rattya J, Pakarinen AJ, Knip M et al. (2001) Early hormonal changes during valproate or carbamazepine treatment: a 3-month study. Neurology 57:440–444PubMedCrossRefGoogle Scholar
  20. Reid G, Hubner MR, Metivier R et al. (2003) Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. Mol Cell 11:695–707PubMedCrossRefGoogle Scholar
  21. Reid G, Metivier R, Lin CY et al. (2005) Multiple mechanisms induce transcriptional silencing of a subset of genes, including oestrogen receptor alpha, in response to deacetylase inhibition by valproic acid and trichostatin A. Oncogene 24:4894–4907PubMedCrossRefGoogle Scholar
  22. Sato Y, Kondo I, Ishida S et al. (2001) Decreased bone mass and increased bone turnover with valproate therapy in adults with epilepsy. Neurology 57:445–449PubMedCrossRefGoogle Scholar
  23. Shang Y, Hu X, DiRenzo J et al. (2000) Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell 103:843–852PubMedCrossRefGoogle Scholar
  24. Sharma D, Fondell JD (2002) Ordered recruitment of histone acetyltransferases and the TRAP/Mediator complex to thyroid hormone-responsive promoters in vivo. Proc Natl Acad Sci USA 99:7934–7939PubMedCrossRefGoogle Scholar
  25. Stenoien DL, Patel K, Mancini MG et al. (2001) FRAP reveals that mobility of oestrogen receptor-alpha is ligand- and proteasome-dependent. Nat Cell Biol 3:15–23PubMedCrossRefGoogle Scholar
  26. Teicher BA, Ara G, Herbst R et al. (1999) The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res 5:2638–2645PubMedGoogle Scholar
  27. Vaisanen S, Dunlop TW, Sinkkonen L et al. (2005) Spatio-temporal activation of chromatin on the human CYP24 gene promoter in the presence of 1alpha,25-Dihydroxyvitamin D3. J Mol Biol 350:65–77PubMedCrossRefGoogle Scholar
  28. Vassilev LT, Vu BT, Graves B et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.European Molecular Biology Laboratory (EMBL)HeidelbergGermany

Personalised recommendations