Epigenetic Regulation of Transcription Factor Promoter Regions by Low-Dose Genistein Through Mitogen-Activated Protein Kinase and Mitogen-And-Stress Activated Kinase 1 Nongenomic Signaling

摘要: The phytoestrogen, genistein at low doses nongenomically activates mitogen-activated protein kinase p44/42 (MAPKp44/42) via estrogen receptor alpha (ERα) leading to proliferation of human uterine leiomyoma cells. In this study, we evaluated if MAPKp44/42 could activate downstream effectors such as mitogen- and stress-activated 1 (MSK1), which then epigenetically modify histone H3 by phosphorylation following a dose (1 μg/ml) genistein. Using hormone-responsive immortalized (ht-UtLM) cells, found that activated MSK1, also increased serine10 (H3S10ph) in ht-UtLM Colocalization phosphorylated MSK1 H3S10ph was evident confocal microscopy cells (r = 0.8533). Phosphorylation both MSK1and abrogated PD98059 (PD), MEK1 inhibitor, thereby supporting genistein’s activation Histone MAPKp44/42. proliferative (estrogenic) phase fibroid tissues, showed immunoexpression compared normal myometrial similar results observed vitro studies low-dose administration. Real-time RT-PCR arrays induction growth-related transcription factor genes, EGR1, Elk1, ID1, MYB (cMyb) with confirmation western blot, MAPK response Additionally, induced associations promoter regions the above factors evidenced Chromatin Immunoprecipitation (ChIP) assays, were inhibited PD. Therefore, modified serine 10, regulated activation. possibly represents mechanism whereby transcriptional occurs exposure.