| First Author | Du C | Year | 2017 |
| Journal | Leukemia | Volume | 31 |
| Issue | 4 | Pages | 945-956 |
| PubMed ID | 27748371 | Mgi Jnum | J:241035 |
| Mgi Id | MGI:5897523 | Doi | 10.1038/leu.2016.285 |
| Citation | Du C, et al. (2017) Estrogen promotes megakaryocyte polyploidization via estrogen receptor beta-mediated transcription of GATA1. Leukemia 31(4):945-956 |
| abstractText | Estrogen is reported to be involved in thrombopoiesis and the disruption of its signaling may cause myeloproliferative disease, yet the underlying mechanisms remain largely unknown. GATA-binding factor 1 (GATA1) is a key regulator of megakaryocyte (MK) differentiation and its deficiency will lead to megakaryoblastic leukemia. Here we show that estrogen can dose-dependently promote MK polyploidization and maturation via activation of estrogen receptor beta (ERbeta), accompanied by a significant upregulation of GATA1. Chromatin immunoprecipitation and a dual luciferase assay demonstrate that ERbeta can directly bind the promoter region of GATA1 and activate its transcription. Steroid receptor coactivator 3 (SRC3) is involved in ERbeta-mediated GATA1 transcription. The deficiency of ERbeta or SRC3, similar to the inhibition of GATA1, leads to the impediment of estrogen-induced MK polyploidization and platelet production. Further investigations reveal that signal transducer and activator of transcription 1 signaling pathway downstream of GATA1 has a crucial role in estrogen-induced MK polyploidization, and ERbeta-mediated GATA1 upregulation subsequently enhances nuclear factor erythroid-derived 2 expression, thereby promoting proplatelet formation and platelet release. Our study provides a deep insight into the molecular mechanisms of estrogen signaling in regulating thrombopoiesis and the pathogenesis of ER deficiency-related leukemia. |
