The Inhibition by Progesterone of Uterine Epithelial Proliferation in the Mouse

Martin, L.; Das, R. M.; Finn, C. A.

doi:10.1677/joe.0.0570549

Cited by 123 publications

(64 citation statements)

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“…To study the molecular mechanism of P 4 inhibition of the E 2 -induced proliferation in the uterine epithelium, a cDNA microarray comparison was performed between mice treated with E 2 and P 4 E 2 . Ovariectomized adult mice were pretreated with P 4 for 3 days before a final combined injection of P 4 and E 2 on the fourth day in regimens that parallel the physiological concentrations (13). The RNA samples obtained were compared with mice given E 2 treatment that mimicked the preovulatory surge of the estrus cycle (14).…”

Section: Resultsmentioning

confidence: 99%

“…However, despite the induction of these markers, no true DNA synthesis could be detected by the incorporation of BrdU. These data suggest that a second pathway (independent of the retinoblastoma one) needs to be activated by E 2 for DNA synthesis to be initiated and that this pathway is also inhibited by P 4 .…”

mentioning

confidence: 83%

“…In mice, E 2 synthesized at proestrus stimulates uterine luminal and glandular epithelial cell proliferation (2). In contrast, P 4 synthesized by corporea lutea formed after mating blocks the E 2 -induced epithelial cell proliferation but permits E 2 to induce a single wave of stromal cell division (3,4). P 4 also induces differentiation of these epithelial cells so that they are receptive to the hatched blastocysts in order that implantation can proceed.…”

mentioning

confidence: 99%

“…These uterine cellular dynamics can be mimicked by administration of exogenous E 2 and P 4 to ovariectomized mice in regimens that parallel their physiological secretion (2,5,6). This hormone treatment provides a controllable model in which to study the mechanism of E 2 induction of cell proliferation in target epithelial tissues and also the action of a physiological inhibitor of cell division, in this case P 4 . These studies are highly relevant because exposure to the mitogenic effects of E 2 is thought to be the major risk factor for the development of endometrial and breast cancer (7).…”

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confidence: 99%

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Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing

Pan

Deng

Pollard

2006

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

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In the uterus, progesterone (P4) acts early in G1 as a physiological inhibitor of estradiol-17␤ (E2)-induced epithelial cell proliferation. Gene expression profiling of uterine epithelial cell RNA isolated 3 h after hormonal treatment of ovariectomized mice revealed the co-coordinate down-regulation by P 4 of >20 genes whose functions are associated with DNA replication. This group included all of the minichromosome maintenance (MCM) proteins that are required for DNA replication licensing. E 2 regulated loading of these MCM proteins onto chromatin in parallel with its induction of DNA synthesis. E 2 caused this chromatin loading by retention of MCM proteins in the nucleus and through the induction of the loading factor Cdt1, which is necessary for the MCM heterohexamer to bind to the origin of DNA replication. P 4 dramatically reduced the binding of the MCMs to chromatin by a number of mechanisms. First, MCM mRNA and protein abundance was downregulated. Second, P 4 inhibited the E2 induction of Cdt1. Third, P4 treatment sequestered the normally nuclear MCM proteins into the cytoplasm. This reduced MCM binding resulted in the complete inhibition of E 2-induced DNA synthesis by P4. These data reveal mechanisms not only for female sex steroid hormone action but also in the regulation of DNA replication licensing.DNA replication ͉ minichromosome maintenance ͉ uterus ͉ cell cycle ͉ microarray I n uteri of mice and women, the female sex steroid hormones estradiol-17␤ (E 2 ) and progesterone (P 4 ) interact to regulate cell proliferation (1). In mice, E 2 synthesized at proestrus stimulates uterine luminal and glandular epithelial cell proliferation (2). In contrast, P 4 synthesized by corporea lutea formed after mating blocks the E 2 -induced epithelial cell proliferation but permits E 2 to induce a single wave of stromal cell division (3, 4). P 4 also induces differentiation of these epithelial cells so that they are receptive to the hatched blastocysts in order that implantation can proceed. These uterine cellular dynamics can be mimicked by administration of exogenous E 2 and P 4 to ovariectomized mice in regimens that parallel their physiological secretion (2,5,6). This hormone treatment provides a controllable model in which to study the mechanism of E 2 induction of cell proliferation in target epithelial tissues and also the action of a physiological inhibitor of cell division, in this case P 4 . These studies are highly relevant because exposure to the mitogenic effects of E 2 is thought to be the major risk factor for the development of endometrial and breast cancer (7).DNA replication needs to be a highly regulated process, and most cells seek to ensure one (and only one) round of replication per cell cycle. DNA synthesis is initiated by the formation of the prereplicative complex (pre-RC) at origins of replication during early G 1 , a process known as replication licensing (8, 9). Pre-RC formation involves the sequential assembly of Ͼ20 replication factors in a process that is largely conserved from yeast ...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 83%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing

Pan

Deng

Pollard

2006

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

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“…Progesterone (P 4 ) inhibits estrogen-induced cell proliferation of the luminal and glandular epithelial compartment (5) and stimulates epithelial differentiation in preparation for embryo implantation. Physiologically and pharmacologically, P 4 is important for prevention of endometrial hyperplasia (6).…”

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confidence: 99%

Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β ^−/− mice

Wada-Hiraike

Hiraike

Okinaga

et al. 2006

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

105

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In this study, we compared the uterine tissue of estrogen receptor (ER)␤ ؊/؊ mice and their WT littermates for differences in morphology, proliferation [the percentage of labeled cells 2 h after BrdUrd injection and EGF receptor (EGFR) expression], and differentiation (expression of progesterone receptor, E-cadherin, and cytokeratins). In ovariectomized mice, progesterone receptor expression in the uterine epithelium was similar in WT and ER␤ ؊/؊ mice, but E-cadherin and cytokeratin 18 expression was lower in ER␤ ؊/؊ mice. The percentage of cells in S phase was 1.5% in WT mice and 8% in ER␤ ؊/؊ mice. Sixteen hours after injection of 17␤-estradiol (E2), the number of BrdUrd-labeled cells increased 20-fold in WT mice and 80-fold in ER␤ ؊/؊ mice. Although ER␣ was abundant in intact mice, after ovariectomy, ER␣ could not be detected in the luminal epithelium of either WT or ER␤ ؊/؊ mice. In both untreated and E2-treated mice, ER␣ and ER␤ were colocalized in the nuclei of many stromal and glandular epithelial cells. However, upon E2 ؉ progesterone treatment, ER␣ and ER␤ were not coexpressed in any cells. In WT mice, EGFR was located on the membranes and in the cytoplasm of luminal epithelium, but not in the stroma. In ER␤ ؊/؊ mice, there was a marked expression of EGFR in the nuclei of epithelial and stromal cells. Upon E2 treatment, EGFR on cell membranes was down-regulated in WT but not in ER␤ ؊/؊ mice. These findings reveal an important role for ER␤ in response to E2 and in the organization, growth, and differentiation of the uterine epithelium.differentiation ͉ proliferation ͉ uterus P roliferation of epithelial cells (1, 2), uterine hyperemia, fluid uptake (termed water imbibition), recruitment of inflammatory leukocytes from the bloodstream into the stromal compartment (3, 4), and the induction of the progesterone receptor (PR) are caused by 17␤-estradiol (E 2 ). Progesterone (P 4 ) inhibits estrogen-induced cell proliferation of the luminal and glandular epithelial compartment (5) and stimulates epithelial differentiation in preparation for embryo implantation. Physiologically and pharmacologically, P 4 is important for prevention of endometrial hyperplasia (6). After the cessation of ovarian function, estrogen replacement is needed for preservation of the skeletal, cardiovascular, and central nervous systems. To oppose the proliferative effects of estrogen on the uterus and reduce the risk of endometrial cancer, progesterone is used together with estrogen in hormone replacement therapy after menopause (7,8).Most of the known actions of estrogen are mediated by the estrogen receptors (ERs) ER␣ and ER␤, both of which bind E 2 and modulate transcription of E 2 -responsive genes (9). A single injection of E 2 results in a synchronized wave of cell proliferation, with DNA synthesis in epithelial cells beginning 6-9 h after E 2 injection and peaking at 12-15 h. DNA synthesis is followed by a wave of cell division (1, 2, 10). P 4 elicits its function through binding to the PR.During the secretory phase of the estrus...

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Subtilisin proprotein convertase‐6 expression in the mouse uterus during implantation and artificially induced decidualization

Wong¹,

Liu²,

Schultz³

et al. 2002

Molecular Reproduction Devel

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During implantation, a balance of factors regulates the invasive properties of the embryo and the anti-invasive properties of uterine decidua. Although antiproteinases such as the metalloproteinase inhibitor TIMP-3 are thought to play critical roles in preventing the overaggressive invasion of trophoblasts, the mechanism of antiproteinase regulation is unknown. Recently, the prohormone convertase SPC-6 has been found to be co-expressed in embryo-proximal decidua in association with TIMP-3. As members of this serine proteinase family are known to activate latent TGFbeta family members which regulate decidual TIMP-3 levels, we sought to characterize the expression of SPC-6 during pregnancy and artificial decidualization. In this study, we demonstrate that the zone of SPC-6 gene expression exhibits a great degree of temporal and spatial overlap with TIMP-3 gene expression in uterine decidua from E5.5 through to E8.5. Like TIMP-3, we demonstrate that SPC-6 expression is induced during the decidual cell response using an in vivo model of artificial decidualization. Both the secreted and membrane bound forms of SPC-6 are expressed throughout the period of decidualization, suggesting that SPC-6 may play multiple roles during this developmental period. This is confirmed by our observation of the movement of SPC-6 expression to the presumptive placental region, as TIMP-3 expression regresses at the implantation site.

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The Inhibition by Progesterone of Uterine Epithelial Proliferation in the Mouse

Cited by 123 publications

References 5 publications

Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing

Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing

Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β ^−/− mice

Subtilisin proprotein convertase‐6 expression in the mouse uterus during implantation and artificially induced decidualization

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The Inhibition by Progesterone of Uterine Epithelial Proliferation in the Mouse

Cited by 123 publications

References 5 publications

Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing

Progesterone blocks estrogen-induced DNA synthesis through the inhibition of replication licensing

Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β −/− mice

Subtilisin proprotein convertase‐6 expression in the mouse uterus during implantation and artificially induced decidualization

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Role of estrogen receptor β in uterine stroma and epithelium: Insights from estrogen receptor β ^−/− mice