DNA binding by estrogen receptor-alpha is essential for the transcriptional response to estrogen in the liver and the uterus

Autor: Jenny Schkoldow, Malcolm G. Parker, Brenda D. Stride, Anette Sommer, Susanne Trölenberg, Günther Schütz, Dörthe L. Ahlbory-Dieker, Henrik Seidel, Christiane Otto, Gabriele Leder, Tim Wintermantel
Rok vydání: 2009
Předmět:
Zdroj: Molecular endocrinology (Baltimore, Md.). 23(10)
ISSN: 1944-9917
Popis: The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor (ER)alpha, which regulates transcription by several mechanisms. Because the tissue-specific effects of some ERalpha ligands may be caused by tissue-specific transcriptional mechanisms of ERalpha, we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver. We used a genetic mouse model that dissects DNA binding-dependent vs. independent transcriptional regulation elicited by ERalpha. The EAAE mutant harbors amino acid exchanges at four positions of the DNA-binding domain (DBD) of ERalpha. This construct was knocked in the ERalpha gene locus to produce ERalpha((EAAE/EAAE)) mice devoid of a functional ERalpha DBD. The phenotype of the ERalpha((EAAE/EAAE)) mice resembles the general loss-of-function phenotype of alphaER knockout mutant mice with hypoplastic uteri, hemorrhagic ovaries, and impaired mammary gland development. In agreement with this phenotype, the expression pattern of the ERalpha((EAAE/EAAE)) mutant mice in liver obtained by genome-wide gene expression profiling supports the observation of a near-complete loss of estrogen-dependent gene regulation in comparison with the wild type. Further gene expression analyses to validate the results of the microarray data were performed by quantitative RT-PCR. The analyses indicate that both gene activation and repression by estrogen-bound ERalpha rely on an intact DBD in vivo.
Databáze: OpenAIRE