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D. J. Mangelsdorf, C. Thummel, M. Beato, P. Herrlich, G. Schütz, K. Umesono, B. Blumberg, P. Kastner, M. Mark, P. Chambon and R. M. Evans, “The Nuclear Receptor Superfamily: The Second Decade,” Cell, Vol. 83, No. 6, 1995, pp. 835-839. doi:10.1016/0092-8674(95)90199-X

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• TITLE: The Transactivating Function 2 (AF-2) of Estrogen Receptor (ER) α Is Indispensable for ERα-Mediated Physiological Responses and AF-1 Activity

  AUTHORS: Yukitomo Arao, Katherine J. Hamilton, Kenneth S. Korach

  KEYWORDS: Knock-In Mouse; SERMs; Antagonist Reversal

  JOURNAL NAME: Open Journal of Endocrine and Metabolic Diseases, Vol.3 No.4B, August 6, 2013

  ABSTRACT: Estrogen has various physiological functions and the estrogen receptor (ER) is a key regulator of those functions. ERα is a ligand-dependent transcription factor and that activity is mediated by the transactivating function-1 (AF-1) in the N-terminal domain and transactivating function-2 (AF-2) in the C-terminal ligand-binding domain. The functions of ERα AF-1 and AF-2 have been characterized by various in vitro experiments, however, there is still less information about the in vivo physiological functions of ERα AF-1 and AF-2. Recently, we established a genetically mutated ERα AF-2 knock-in mouse (AF2ERKI) that possessed L543A, L544A mutated-ERα. This AF-2 core mutation disrupted AF-2 function and resulted in ERα null phenotypes. This mouse model revealed that proper AF-2 core structure and function were indispensable for ERα-mediated physiological responses and AF-1 functionality. AF2ER mutation reverses the ERα antagonists to agonists and that activity is mediated by AF-1 solely. The pure antagonist, ICI182780/fulvestrant, activated several estrogen-mediated physiological responses in the AF2ERKI mouse. The AF2ERKI mouse model will be useful to discern estrogen physiological functions which involve AF-1.