Identification of Murine Uterine Genes Regulated in a Ligand-Dependent Manner by the Progesterone Receptor

Jeong, Jaewook; Lee, Kevin Y.; Kwak, Ihn‐Sil; White, Lisa D.; Hilsenbeck, Susan G.; Lydon, John P.; DeMayo, Francesco J.

doi:10.1210/en.2005-0016

Cited by 140 publications

(135 citation statements)

References 47 publications

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“…Microarray analysis was performed by Affymetrix murine genome U74Av2 mouse oligonucleotide arrays (Affymetrix) as previously described (30). All experiments were repeated 3 times.…”

Section: Methodsmentioning

confidence: 99%

“…The identification of P4-regulated pathways in the uterus is thus crucial for understanding the impairments that underlie disruption of steroid hormone control of uterine cell proliferation and differentiation. In previous studies, we have identified P4-regulated genes using microarray analysis on P4-treated PRKO uteri (30). We have identified Mig-6 as a target of SRC-1 and PR in the uterus.…”

Section: Downregulation Of Mig-6 In Human Endometrialmentioning

confidence: 98%

“…These genes were Mig-6, Myc, Il13ra2, and an EST. The EST was not analyzed further because it did not have any known homologous gene and its expression was not PR-dependent, based on our previous microarray data (30).…”

Section: Identification Of P4 and Src-1 Regulated Genes Using Microarraymentioning

confidence: 99%

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Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Jeong

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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118

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Normal endometrial function requires a balance of progesterone (P4) and estrogen (E2) effects. An imbalance caused by increased E2 action and/or decreased P4 action can result in abnormal endometrial proliferation and, ultimately, endometrial adenocarcinoma, the fourth most common cancer in women. We have identified mitogen-inducible gene 6 (Mig-6) as a downstream target of progesterone receptor (PR) and steroid receptor coactivator (SRC-1) action in the uterus. Here, we demonstrate that absence of Mig-6 in mice results in the inability of P4 to inhibit E2-induced uterine weight gain and E2-responsive target genes expression. At 5 months of age, the absence of Mig-6 results in endometrial hyperplasia. Ovariectomized Mig-6 d/d mice exhibit this hyperplastic phenotype in the presence of E2 and P4 but not without ovarian hormone. Ovariectomized Mig-6 d/d mice treated with E2 developed invasive endometrioid-type endometrial adenocarcinoma. Importantly, the observation that endometrial carcinomas from women have a significant reduction in MIG-6 expression provides compelling support for an important growth regulatory role for Mig-6 in the uterus of both humans and mice. This demonstrates the Mig-6 is a critical regulator of the response of the endometrium to E2 in regulating tissue homeostasis. Since Mig-6 is regulated by both PR and SRC-1, this identifies a PR, SRC-1, Mig-6 regulatory pathway that is critical in the suppression of endometrial cancer.estrogen ͉ endometrial cancer ͉ progesterone ͉ progesterone receptor ͉ SRC-1

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“…Microarray analysis was performed by Affymetrix murine genome U74Av2 mouse oligonucleotide arrays (Affymetrix) as previously described (30). All experiments were repeated 3 times.…”

Section: Methodsmentioning

confidence: 99%

Section: Downregulation Of Mig-6 In Human Endometrialmentioning

confidence: 98%

See 1 more Smart Citation

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Jeong

Lee

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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118

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“…On the other hand, perturbations in the maternal decidual response inevitably lead to pregnancy complications, most prevalent of which is miscarriage 2 . SGK1, a serine/threonine protein kinase homologous to AKT, is rapidly induced in response to a rise in progesterone levels in both human and mouse endometrium, first in epithelial cells and then in the decidualizing stroma [13][14][15] . SGK1 is a key regulator of sodium transport in mammalian epithelia, most prominently through its ability to directly activate epithelial sodium channel (ENaC) and to enhance their expression by inhibiting the ubiquitin ligase NEDD4-2 5,6 .…”

mentioning

confidence: 99%

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

Salker

Christian

Steel

et al. 2011

Nat Med

174

140

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Conflict of interest:The authors have declared that no conflict of interest exists.Nonstandard abbreviations used: SGK1, serum-and glucocorticoid-inducible kinase 1; RPL, recurrent pregnancy loss; ENaC, epithelial sodium channel; HESC, human endometrial stromal cells; ROS, reactive oxygen species; IVF, in vitro fertilization; dpc, days post coitus. 2Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations 1,2 .Analysis of mid-secretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival [3][4][5][6] , is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional significance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling, and abolished embryo implantation.By contrast, implantation was unhindered in Sgk1 -/-mice but pregnancy was often complicated by bleeding at the decidual-placental interface, fetal growth retardation and subsequent demise. Compared to WT animals, pregnancy-dependent induction of genes involved in oxidative stress defenses was grossly impaired in Sgk1 -/-mice. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from RPL subjects and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.The sustained rise in postovulatory circulating progesterone levels renders the endometrium transiently receptive to embryo implantation. This 'window of implantation', confined to 2 to 4 days during the mid-secretory phase of the cycle, enables the embryo to contact and stably adhere to the endometrial luminal epithelium before invading the decidualizing stroma 7-9 . Decidualization, which denotes the transformation of stromal fibroblasts into specialized secretory decidual cells, is indispensable for pregnancy as it governs local immune responses, controls trophoblast invasion, and protects the conceptus against a variety of physiological stressors associated with pregnancy [10][11][12] . Failure of the endometrium to express a receptive phenotype is a major cause of conception delay and IVF 3 treatment failure. On the other hand, perturbations in the maternal decidual response inevitably lead to pregnancy complications, most prevalent of which is miscarriage 2 . SGK1, a serine/threonine protein kinase homologous to AKT, is rapidly induced in response to a rise in progesterone levels in both human and mouse endometrium, first in epithelial cells and then in the decidualizing st...

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“…Several investigators reported the genes regulated by progesterone in the uterus with cDNA microarray [8,9]. Recently, gene targeting was used to create knockout mice for PR (PR knockout mouse: PRKO mouse) [10,11].…”

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confidence: 99%

Evidence for the Expression of Alcohol Dehydrogenase Class I Gene in Rat Uterus and Its Up-regulation by Progesterone

et al. 2008

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Abstract. The endometrium is one of the target tissues of the ovarian steroid hormones, estrogen and progesterone. In order to elucidate the mechanism of gene regulation in the endometrium, suppressive subtraction hybridization was performed to isolate the candidate genes controlled by progesterone in rat uterus. Alcohol dehydrogenase (ADH) class I gene was one of the candidate genes. Here we investigated the expression and regulation of ADH class I gene in rat uterus. The mRNA of ADH class I was detected in uterus by RT-PCR using specific primers. Using specific probe for ADH class I, in situ hybridization was performed to investigate localization in rat uterus. Positive signals were detected in the endometrial stromal cells of rat uterus by in situ hybridization and were not detected in endometrial epithelial cells and myometrium in rat uterus. Ovariectomized rats were treated with 17-β estradiol and progesterone and the uteri of these rats were used for Northern blot analysis and assay of the ADH activity. Northern blot analysis revealed that the expression of ADH class I mRNA in rat uteri was up-regulated approximately two-fold after progesterone treatment, but not estrogen. Likewise, ADH activity was approximately two-fold higher in progesterone-treated rat uteri compared with controls. This study demonstrated that ADH class I gene is progesterone-responsive in the uterus. This implies that progesterone might be involved with retinoic acid synthesis in the uterus, since ADH is the key enzyme for retinoic acid synthesis.

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Identification of Murine Uterine Genes Regulated in a Ligand-Dependent Manner by the Progesterone Receptor

Cited by 140 publications

References 47 publications

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

Evidence for the Expression of Alcohol Dehydrogenase Class I Gene in Rat Uterus and Its Up-regulation by Progesterone

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