The Egr family of zinc finger transcription factors consisting of 4 members (Egr1 to Egr4) regulates critical genetic programs involved in cellular growth, differentiation, and function. They are co-ex-pressed in many different tissues, suggesting that they may have some redundant functions. While it is clear that estrogen regulates Egr1 in estrogen sensitive breast cancer cells, function of Egr1 and mechanisms by which estrogen (E2) and/or progesterone (P4) regulates Egr1 in uterus still remain unexplored. Thus, we have examined regulatory mechanisms by which Egr1 is regulated in the uterus and abnormal uterine phenotypes of Egr1(－/－) mice. Eight-week-old female mice were ovariectomized (OVX) and rested for a week. Uteri of OVX mice treated with various concentrations of E2 and/or other hormones were collected at 2 h after hormone treatment unless otherwise indicated. ICI 182,780 [estrogen receptor (ER) antagonist] or RU486 [progesterone receptor (PR) antagonist] was injected to OVX mice 30 min prior to hormone treatments. OVX Egr1(+/+) and Egr1(－/－) mice were treated with E2 and/or P4 to examine expression patterns of genes important for estrogen responses, and steroid hormone-induced cell proliferation in the uterus. Collected uteri were utilized for RT-PCR, realtime RT-PCR, Western blotting and histological analyses. Egr1 mRNA was rapidly induced with the highest level at 2h after E2 treatment and gradually deceased to basal levels at 12 h. Pretreatment of ICI 182,780 significantly reduced E2-induced increase of Egr1. However, an agonist for GPR30, a membrane estrogen receptor failed to induce mRNA expression of Egr1, suggesting that E2-dependent Egr1 transcription is mainly regulated via nuclear estrogen receptor, ER. P4 effectively dampened E2-dependent Egr1 transcription and its antagonistic effects were partially interfered with RU486 pretreatment. Histological analyses with BrdU incorporation experiments showed that vascular permeability (an early estrogen response) but not cell proliferation (a late response) was significantly impaired in the uteri of E2 treated OVX Egr1(－/－) mice. Interestingly, some genes involved in early estrogen responses such as Bip and HIF-1a but not those in late responses are dysregulated in uteri of Egr1(－/－) mice. Collectively, our results show that E2 transiently induces Egr1 via activation of nuclear ER. P4 antagonizes E2-dependent Egr1 regulation via PR. Impaired early estrogenic responses in Egr1(－/－) uteri could be due to aberrant gene expression affected by loss of Egr1 which act as a master regulator of estrogen actions in the uterus.-ex

• Jung Ah Yoon(Department of Biomedical Science, CHA University, Fertility Center of CHA Gangnam Medical Center, CHA University)
• Haengseok Song(Department of Biomedical Science, CHA University, Fertility Center of CHA Gangnam Medical Center, CHA University)