Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Ivanga, Mahinè; Labrie, Yvan; Calvo, Ézéquiel; Belleau, Pascal; Martel, Céline; Luu‐The, Van; Morissette, Jean; Labrie, Fernand; Durocher, Francine

doi:10.1152/physiolgenomics.00291.2005

Cited by 27 publications

(32 citation statements)

References 71 publications

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“…Other studies in IGF1-null mutant mice showed that IGF1 is necessary for epithelial cells of prepubertal uteri in response to E 2 to progress through G 2 but not for their traverse through G 1 (23). In a recent transcriptome analysis, the transcripts of multiple genes associated with the IGF1 pathway were affected in response to E 2 , further suggesting that this pathway is regulated by this hormone (24).…”

Section: Discussionmentioning

confidence: 96%

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Zhu¹,

Pollard

2007

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

118

108

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Estradiol-17␤ (E2) causes cell proliferation in the uterine epithelium of mice and humans by signaling through its transcription factor receptor ␣ (ER␣). In this work we show that this signaling is mediated by the insulin-like growth factor 1 receptor (IGF1R) expressed in the epithelium, whose activation leads to the stimulation of the phosphoinositide 3-kinase/protein kinase B pathway leading to cyclin D1 nuclear accumulation and engagement with the canonical cell cycle machinery. This cyclin D1 nuclear accumulation results from the inhibition of glycogen synthase kinase 3␤ (GSK3␤) activity caused by an inhibitory phosphorylation by protein kinase B. Once the IGF1 pathway is activated, inhibition of ER signaling demonstrates that it is independent of ER. Inhibition of GSK3␤ in the absence of E2 is sufficient to induce uterine epithelial cell proliferation, and GSK3␤ is epistatic to IGF1 signaling, indicating a linear pathway from E 2 to cyclin D1. Exposure to E2 is the major risk factor for endometrial cancer, suggesting that downstream activation of this IGF1-mediated pathway by mutation could be causal in the progression to ER-independent tumors.cell cycle ͉ cyclin D ͉ estrogen ͉ glycogen synthase kinase 3␤(GSK3␤) ͉ estrogen receptor T he adult mouse and human uterus undergoes waves of cell proliferation that are regulated by estradiol-17␤ (E 2 ) and progesterone (P 4 ). In both species, E 2 induces cell proliferation in the luminal and glandular epithelium, but in contrast to mice the human stroma also undergoes proliferation during this so-called proliferative phase (1). P 4 synthesized cyclically in the human or in response to copulation in the mouse inhibits this epithelial cell proliferation but primes the stromal cells to respond to E 2 by cell division (1). Because Ͼ50% of women seek medical advice due to uterine bleeding disorders, many of which are associated with proliferation at least once in their lives, and because E 2 is the major risk factor for endometrial and breast adenocarcinomas thought to be the result of the continuous stimulation of cell proliferation (1, 2), it is essential to understand the mechanism of action of these hormones in inducing cell division.In most cell types the entry into DNA synthesis is regulated by the sequential activity of cyclins and their attendant cyclindependent kinases (CDK) in phosphorylating and inactivating the members of the Rb family of proteins (3). These cyclin/CDKs are, in turn, regulated by the expression of a variety of cyclindependent inhibitors that fall into two classes the CIP/KIP family and the pl6 ink4 family, by phosphorylation of activating and inhibitory sites, as well as by their subcellular localization. In most cases, the initial sensing of external mitogenic stimuli is through altering the activity of D-type cyclins and their cognate CDK4 and CDK6 kinases (4, 5), which is also true in the uterine epithelium of mice in response to E 2 . But in contrast to the mitogenic responses of cells to E 2 in culture, the level of cyclin D1 does not ...

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Section: Discussionmentioning

confidence: 96%

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Zhu¹,

Pollard

2007

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

118

108

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“…Both hormones, particularly E2 after 4h, provoke a major influx of fluid into the uterus, and this increased vascular permeability is in part due to an increased mRNA expression of the vascular endothelial growth factor (VEGF) [18]. Indeed, in our previous studies VEGF mRNA expression was up-regulated by 6.7-fold and 3-fold at 3h following E2 or DHT administration, respectively [4,20], which supports its involvement in the regulation of vascular permeability.…”

Section: Discussionmentioning

confidence: 60%

“…The quality of RNA was analyzed on an Agilent 2100 Bioanalyzer (Agilent Technologies Inc, Santa Clara, CA). First-strand cDNA synthesis was accomplished using 5 µg of isolated RNA as reported previously [20]. The resulting products were purified with QIA quick PCR purification kits (QIAGEN, Valencia, CA).…”

Section: Quantitative Real -Time Pcr (Qrt-pcr)mentioning

confidence: 99%

“…Reagents were obtained from the same company and used as described by the manufacturer. PCR amplification and reading of the fluorescence signal was performed as previously described [4,20,39]. Data calculation and normalization were performed using second derivative and double correction method as described previously [39], and using the housekeeping gene hypoxanthine guanine phosphoribosyl transferase 1 (Hprt1).…”

Section: Quantitative Real -Time Pcr (Qrt-pcr)mentioning

confidence: 99%

“…Moreover, the greater risk of breast cancer, deleterious effects on cardiovascular systems and other negative effects attributed to progestins [9,10] reinforces the use of a combination of estrogens and androgens as HRT in menopausal women [11][12][13]. In the mouse, while the estrogenic stimulation of proliferation of uterine epithelial and stromal cell growth and differentiation is well documented [14][15][16][17][18][19][20] the observation that DHT also exerts modulatory effects on these cells is known but not elucidated [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway Components in the Mouse Uterus Following Hormonal Steroid Treatments

2012

Endocrinol Metab Synd

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The uterus is a hormone-dependent organ under the control of estrogens, progestins and androgens. The actions of estradiol (E2) and progesterone on uterine physiology are well documented, while active androgens such as testosterone and dihydrotestosterone (DHT) are now also recognized to exert an important role to appropriately maintain the cyclical changes of the endometrium.Based on our previous observations that DHT modulates GADD45g and the expression of specific cell cycle genes, the aim of this study was to identify the specific uterine cell types in which these cell cycle genes are modulated by hormonal steroids.Using in situ hybridization and quantitative RT-PCR (QRT-PCR), the localization and measurement of mRNA expression of key cell cycle genes responding to E2 and DHT were performed in the uterus of ovariectomized mice. Interestingly, in situ hybridization experiments demonstrate that Gadd45g mRNA is detected early and strongly in stromal cells only, indicating that the early cell cycle arrest induced by DHT and E2 in the mouse uterus occurs in this compartment. On the other hand, the cell cycle stimulation represented by the late increase of Ccnb1, Cdc2a and Cdc25c gene expression is located exclusively in the glandular and luminal epithelial cells. QRT-PCR experiments confirm the regulation of mRNA expression observed following in situ hybridization. Surprisingly, both hormones appear to trigger effects in the same direction on cell cycle progression, with androgens inducing a lower modulation of gene expression levels. Additional experiments using the human uterine Ishikawa cell line confirmed the implication of the estrogen receptor in the GADD45g up-regulation following treatment with E2 while the regulation triggered by DHT is less clear. These observations illustrate clearly the stroma-epithelium interactions, which finely regulate the uterine physiology via paracrine mechanisms. Additional investigations are definitely needed to determine the exact role played by androgens in mouse uterine growth and differentiation.

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Fine temporal analysis of DHT transcriptional modulation of the ATM/Gadd45g signaling pathways in the mouse uterus

Ivanga

Labrie

Calvo

et al. 2008

Molecular Reproduction Devel

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In rodents, the uterus of a mature female undergoes changes during the uterine cycle, under the control of steroid hormones. 5alpha-Dihydrotestosterone (DHT) is recognized to play an important role in the regulation of androgen action in normal endometrium. Using microarray technology, a screening analysis of genes responding to DHT in the uterus of ovariectomized mice, has allowed us to highlight multiple genes of the ATM/Gadd45g pathway that are modulated following exposure to DHT. Two phases of regulation were identified. In the early phase, the expression of genes involved in the G2/M arrest is rapidly increased, followed by the repression of genes of the G1/S checkpoint, and by the induction of transcriptional regulators. Later, i.e. from 12 to 24 hr, genes involved in G2/M transition, cytoarchitectural and lipid-related genes are stimulated by DHT while immunity-related genes appear to be differentially regulated by the hormone. These results show that a physiological dose of DHT induces the transcription of genes promoting the cell cycle progression in mice. Profile determination of temporal uterine gene expression at the transcriptional level enables us to suggest that the DHT modulation of genes involved in ATM/Gadd45g signaling in an ATM- or p53-independent manner, could play an important role in the cyclical changes of uterine cells in the mouse uterus.

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Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus

Cited by 27 publications

References 71 publications

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Estradiol-17β regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling

Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway Components in the Mouse Uterus Following Hormonal Steroid Treatments

Fine temporal analysis of DHT transcriptional modulation of the ATM/Gadd45g signaling pathways in the mouse uterus

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