Repressor of Estrogen Receptor Activity (REA) is a gene dose-dependent coregulator protein affecting estrogen signaling and cell survival

estrogen;transcription;coregualator;uterus;mammary gland

Park, Sung Hee

关键词: estrogen;    transcription;    coregualator;    uterus;    mammary gland;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/24368/PARK_SUNGHEE.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Repressor of Estrogen Receptor Activity (REA) is an evolutionarily conserved protein with established roles in multiple, essential cellular processes including transcription, mitochondrial biogenesis and replicative senescence. Previous reports suggest that REA is a multifunctional protein with important biological activity. However, despite increasing information, the physiological functions and regulatory mechanisms of REA are still incompletely understood. To gain insight into the role of REA in estrogen responsive tissues, we investigated its function in both the uterus and mammary gland by conditional deletion of the REA gene, because the conventional knockout of REA is embryonic lethal. To this end, we generated REAf/f mice and crossed them with PR-Cre knock-in mice as well as WAP-Cre transgenic mice, thereby creating conditional REA knockouts under the control of either the progesterone receptor or whey acidic protein promoter. We found that complete REA loss of function resulted in severe defects in both uterine and mammary gland development and functional activities. REA deletion in the uterus resulted in infertility due to severely compromised uterine development and function. Ablation of REA in the mammary gland resulted in impaired mammary gland ductal and alveolar morphogenesis, leading to reduced body size and growth of the offspring nursed by females lacking both REA alleles. These observations demonstrate that REA is critical for normal uterine and mammary gland function. By contrast, 50% reduction of REA via heterozygous inactivation enhanced estradiol (E2) response in both the uterus and mammary gland. Heterozygous REA mutant mice treated with E2 developed abnormally large uteri due to increased E2-mediated uterine epithelial cell proliferation and increased fluid imbibition. Additionally, mammary ductal elongation during puberty was accelerated in heterozygous mice. Our findings indicate that REA possesses dose-dependent activity, showing a positive modulatory role in heterozygous REA animals and a negative modulatory role in homozygous REA animals. These studies in animals with conditional loss of both or only one allele of REA highlight the importance of the correct gene dosage of REA for normal uterine and mammary gland function.