Yoo Jung-Yoon, Kim Tae Hoon, Lee Jae Hee, Dunwoodie Sally L, Ku Bon Jeong, Jeong Jae-Wook
Department of Obstetrics, Gynecology & Reproductive Biology, Michigan State University, Grand Rapids, MI, United States.
Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia; St. Vincent's Clinical School and the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, New South Wales 2033, Australia.
Biochem Biophys Res Commun. 2015 Jul 10;462(4):409-14. doi: 10.1016/j.bbrc.2015.04.146. Epub 2015 May 12.
Mitogen inducible gene 6 (Mig-6) is an important mediator of progesterone (P4) signaling to inhibit estrogen (E2) signaling in the uterus. Ablation of Mig-6 in the murine uterus leads to the development of endometrial hyperplasia and E2-induced endometrial cancer. To identify the molecular pathways regulated by Mig-6, we performed microarray analysis on the uterus of ovariectomized Mig-6(f/f) and PGR(cre/+)Mig-6(f/f) (Mig-6(d/d)) mice treated with vehicle or P4 for 6 h. The results revealed that 772 transcripts were significantly regulated in the Mig-6(d/d) uterus treated with vehicle as compared with Mig-6(f/f) mice. The pathway analysis showed that Mig-6 suppressed the expression of gene-related cell cycle regulation in the absence of ovarian steroid hormone. The epithelium of Mig-6(d/d) mice showed a significant increase in the number of proliferative cells compared to Mig-6(f/f) mice. This microarray analysis also revealed that 324 genes are regulated by P4 as well as Mig-6. Cited2, the developmentally important transcription factor, was identified as being regulated by the P4-Mig-6 axis. To determine the role of Cited2 in the uterus, we used the mice with Cited2 that were conditionally ablated in progesterone receptor-positive cells (PGR(cre/+)Cited2(f/f); Cited2(d/d)). Ablation of Cited2 in the uterus resulted in a significant reduction in the ability of the uterus to undergo a hormonally induced decidual reaction. Identification and analysis of these responsive genes will help define the role of P4 as well as Mig-6 in regulating uterine biology.
丝裂原诱导基因6（Mig-6）是孕酮（P4）信号传导以抑制子宫中雌激素（E2）信号传导的重要介质。在小鼠子宫中敲除Mig-6会导致子宫内膜增生和E2诱导的子宫内膜癌的发生。为了确定受Mig-6调控的分子途径，我们对用赋形剂或P4处理6小时的去卵巢Mig-6（f/f）和PGR（cre/+）Mig-6（f/f）（Mig-6（d/d））小鼠的子宫进行了微阵列分析。结果显示，与Mig-6（f/f）小鼠相比，用赋形剂处理的Mig-6（d/d）子宫中有772个转录本受到显著调控。通路分析表明，在没有卵巢类固醇激素的情况下，Mig-6抑制了与细胞周期调控相关的基因表达。与Mig-6（f/f）小鼠相比，Mig-6（d/d）小鼠的上皮细胞增殖细胞数量显著增加。该微阵列分析还显示，有324个基因受P4以及Mig-6调控。Cited2是一种在发育中起重要作用的转录因子，被确定受P4-Mig-6轴调控。为了确定Cited2在子宫中的作用，我们使用了在孕激素受体阳性细胞中条件性敲除Cited2的小鼠（PGR（cre/+）Cited2（f/f）；Cited2（d/d））。子宫中Cited2的敲除导致子宫对激素诱导的蜕膜反应能力显著降低。对这些反应性基因的鉴定和分析将有助于明确P4以及Mig-6在调节子宫生物学中的作用。
