Bip Is a Molecular Link between the Phase I and Phase II Estrogenic Responses in Uterus

Ray, Subhankar; Hou, Xiaonan; Zhou, Han-E; Wang, Haibin; Das, Sanjoy K.

doi:10.1210/me.2006-0046

Cited by 27 publications

(33 citation statements)

References 43 publications

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“…The rapid up-regulation of GRP78 observed here is in line with our previous finding regarding early onset endoplasmic reticulum stress response related to a local P450-catalyzed bioactivation of toxicants in rodents (Franzén and Brittebo, 2005). However, 17␤-estradiol may up-regulate GRP78 in the rodent uterus, and it cannot be excluded that the observed up-regulation of GRP78 in human endometrial glands may be related to tamoxifen's estrogenic properties (Ray et al, 2006).…”

Section: Andersson Et Alsupporting

confidence: 91%

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

Andersson

Helmestam²,

Żebrowska³

et al. 2009

Drug Metab Dispos

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Section: Andersson Et Alsupporting

confidence: 91%

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

Andersson

Helmestam²,

Żebrowska³

et al. 2009

Drug Metab Dispos

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“…At different times after the last E 2 injection they were killed and their uteri fixed for IHC, or the uterine epithelium prepared and processed for Western blotting or ChIP as described (48). Ishikawa and T47D cells were cultured and transfected with Mcm2 promoter luciferase constructs and luminescence measure.…”

Section: Methodsmentioning

confidence: 99%

“…Ishikawa and T47D cells were cultured and transfected with Mcm2 promoter luciferase constructs and luminescence measure. Mice or cells were infected with Adenovirus expressing KLF15 or cells with a cDNA expressing KLF4 (48). All data were repeated at least three times and statistical analysis was performed using Prism 5.…”

Section: Methodsmentioning

confidence: 99%

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Ray

Pollard²

2012

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

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In the epithelial compartment of the uterus, estradiol-17β (E 2 ) induces cell proliferation while progesterone (P 4 ) inhibits this response and causes differentiation of the cells. In this study, we identified the mechanism whereby E 2 and P 4 reciprocally regulate the expression of minichromosome maintenance (MCM)-2, a protein that is an essential component of the hexameric MCM-2 to 7 complex required for DNA synthesis initiation. We show in the uterine epithelium that Kruppel-like transcription (KLF) factors, KLF 4 and 15, are inversely expressed; most importantly, they bind to the Mcm2 promoter under the regulation of E 2 and P 4 E 2 , respectively. After P 4 E 2 exposure and in contrast to E 2 treated mice, the Mcm2 promoter displays increased histone 3 (H3) methylation and the recruitment of histone deacetylase 1 and 3 with the concomitant deacetylation of H3. This increased methylation and decreased acetylation is associated with an inhibition of RNA polymerase II binding, indicating an inactive Mcm2 promoter following P 4 E 2 treatment. Using transient transfection assays in the Ishikawa endometrial cell line, we demonstrate that Mcm2 promoter activity is hormonally stimulated by E 2 and that KLF15 inhibits this E 2 enhanced transcription. KLF15 expression also blocks Ishikawa cell proliferation through inhibition of MCM2 protein level. Importantly, in vivo expression of KLF15 in an estrogenized uterus mimics P 4 's action by inhibiting E 2 -induced uterine epithelial MCM-2 expression and DNA synthesis. KLF15 is therefore a downstream physiological mediator of progesterone's cell cycle inhibitory action in the uterine epithelium.endometrium | implantation | menstrual cycle | endometriosis E stradiol-17β (E 2 ) and progesterone (P 4 ) directs uterine preparation for pregnancy. These hormones synthesized cyclically in humans cause a sequential series of proliferative and differentiation events in the uterine stroma and epithelium that result in the epithelium being receptive to the blastocyst for attachment and subsequent implantation (1). Despite this close control of uterine cell proliferation, aberrant proliferative conditions of the human endometrium are common. For example, endometrial polyps and endometriosis are caused by inappropriate proliferation of the uterus, while unopposed estrogen stimulation is associated with menstrual irregularities and endometrial hyperplasia/adenocarcinoma (2). Endometrial cancer is the most common female genital tract malignancy and is responsible for 6% of cancer deaths of women in the United States and more worldwide (3). However, the molecular mechanisms underlying these pathologies are still obscure, as are the molecular mechanisms involved in normal hormonal regulation of cell proliferation in the endometrium, which is essential for successful pregnancy (4).The mouse uterus provides a unique in vivo model to study the regulation of epithelial cell proliferation as the physiological actions of E 2 and P 4 E 2 can be recapitulated in ovariectomized animals by treat...

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“…The generation and infection of the replication-defective adenovirus particles for immunoglobulin heavy chain binding protein (Bip)-antisense [rAdBip(As)] and replication-defective adenovirus particles for green fluorescent protein (GFP) control (rAdGFP) were followed, as previously described (20).…”

Section: Adenovirus Particles and Infectionmentioning

confidence: 99%

“…In mice, because the uteri on d 4 are already primed with E2 and P4 and the uterine epithelial and stromal cells collected on this day of pregnancy undergo manipulation by hormones in culture (20,28), the objective to establish epithelial-stromal cocultures was primarily dependent on d-4 uterine tissues. In our initial studies, the purity of uterine primary epithelial and stromal cells in culture was determined by morphologic observations using light microscopy, as well as by confocal analyses of cell-specific markers.…”

Section: Analysis Of Individual Uterine Primary Cell Culturesmentioning

confidence: 99%

Mouse Primary Uterine Cell Coculture System Revisited: Ovarian Hormones Mimic the Aspects of in Vivo Uterine Cell Proliferation

Chung

Das

2011

Endocrinology

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Previously, the uterine epithelial-stromal coculture system had limited success mimicking in vivo ovarian hormone-dependent cell-specific proliferation. Here, we established a mouse primary uterine coculture system, in which cells collected in pseudopregnancy specifically on d 4 are conducive to supporting hormone-induced cell-specific proliferation. When two cell types are placed in coculture without direct contact via cell culture inserts (nonadjacent), as opposed to with contact (adjacent), epithelial cells exhibit significant proliferation by estradiol-17␤ (E2), whereas progesterone in combination with E2 caused inhibition of epithelial cell proliferation and a major shift in proliferation from epithelial to stromal cells. Epithelial cell integrity, with respect to E-cadherin expression, persisted in nonadjacent, but not adjacent, conditions. In subsequent studies of nonadjacent cocultures, localization of estrogen receptor (ER)␣ and progesterone receptor (PR), but not ER␤, appeared to be abundant, presumably indicating that specific ER or PR coregulator expression might be responsible for this difference. Consistently, an agonist of ER␣, but not ER␤, was supportive of proliferation, and antagonists of ER or PR totally eliminated cell-specific proliferation by hormones. RT-PCR analyses also revealed that hormone-responsive genes primarily exhibit appropriate regulation. Finally, suppression of immunoglobulin heavy chain binding protein, a critical regulator of ER␣ signaling, in epithelial and/or stromal cells caused dramatic inhibition of E2-dependent epithelial cell proliferation, suggesting that a molecular perturbation approach is applicable to mimic in vivo uterine control. In conclusion, our established coculture system may serve as a useful alternative model to explore in vivo aspects of cell proliferation via communication between the epithelial and stromal compartments under the direction of ovarian hormones. (Endocrinology 152: 3246 -3258, 2011) T he uterus is composed of heterogeneous cell types that respond uniquely to estradiol-17␤ (E2) and progesterone (P4). In the adult ovariectomized mouse uterus, E2 stimulates proliferation of luminal and glandular epithelia, whereas in the stroma, this process requires P4 and is potentiated by E2 (1, 2). P4 also plays a major role in the inhibition of E2-induced epithelial cell proliferation (1, 2). A similar hormonal action is also revealed in the early pregnancy of mice. For example, preovulatory ovarian estrogen directs epithelial cell proliferation on d 1 and 2 of pregnancy, whereas on d 3, P4 from newly formed corpora lutea initiates proliferation of stromal cells, but inhibition of epithelial cell proliferation; this is further potentiated by the preimplantation estrogen secretion on d 4 (2, 3). It has been widely viewed that ovarian steroid hormones control uterine cell proliferation and differentiation via alteration of cell-cell communication signaling and gene regulation primarily to restore uterine receptivity for the onset of embryo implantation ...

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Bip Is a Molecular Link between the Phase I and Phase II Estrogenic Responses in Uterus

Cited by 27 publications

References 43 publications

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Mouse Primary Uterine Cell Coculture System Revisited: Ovarian Hormones Mimic the Aspects of in Vivo Uterine Cell Proliferation

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