Mig-6 regulates endometrial genes involved in cell cycle and progesterone signaling

JY Yoo, TH Kim, JH Lee, SL Dunwoodie, BJ Ku… - Biochemical and …, 2015 - Elsevier
Biochemical and biophysical research communications, 2015Elsevier
Abstract 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 …
Abstract
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-6f/f and PGRcre/+Mig-6f/f (Mig-6d/d) mice treated with vehicle or P4 for 6 h. The results revealed that 772 transcripts were significantly regulated in the Mig-6d/d uterus treated with vehicle as compared with Mig-6f/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-6d/d mice showed a significant increase in the number of proliferative cells compared to Mig-6f/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 (PGRcre/+Cited2f/f; Cited2d/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.
Elsevier