scholarly journals Hormone-Induced Expression of Tumor Necrosis Factor α-Converting Enzyme/A Disintegrin and Metalloprotease-17 Impacts Porcine Cumulus Cell Oocyte Complex Expansion and Meiotic Maturation via Ligand Activation of the Epidermal Growth Factor Receptor

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6164-6175 ◽  
Author(s):  
Yasuhisa Yamashita ◽  
Ikkou Kawashima ◽  
Yoshiari Yanai ◽  
Masahide Nishibori ◽  
JoAnne S. Richards ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Small Interfering Rna ◽  
Egf Receptor ◽  
Cumulus Cells ◽  
Meiotic Maturation ◽  
Converting Enzyme ◽  
Epidermal Growth ◽  
Oocyte Meiotic Maturation ◽  
Interfering Rna

The epidermal growth factor (EGF)-like growth factors, amphiregulin (AREG) and epiregulin (EREG), are expressed in murine cumulus oocyte complexes (COCs) where they impact the function of cumulus cells and oocyte maturation during LH-mediated ovulation. Because TNFα-converting enzyme (TACE)/a disintegrin and metalloprotease-17 (ADAM17) is essential for ectodomain shedding of AREG and EREG from the surface of other cell types, the expression and function of TACE/ADAM17 was analyzed in a porcine COC culture system in which FSH- and LH-mediated expansion and oocyte meiotic maturation have been well characterized and shown to occur between 20 and 40 h. In this model, Areg, Ereg, and Tace/Adam17 mRNAs increased significantly with maximal levels observed between 5 and 20 h of culture with FSH plus LH. TACE/ADAM17 protein and protease activity were up-regulated markedly at 10 h and maintained to 40 h. Treatment of COCs with the TACE/ADAM17-selective inhibitor TNFα-processing inhibitor-2 (TAPI-2) significantly suppressed in a time-dependent manner downstream targets of EGF receptor activation such as ERK1/2 phosphorylation, Ptgs2, Has2, and Tnfaip6 mRNA expression, hormone-induced COC expansion, and meiotic maturation of the oocytes. Addition of EGF to COCs cultured in the presence of FSH/LH reversed the inhibitory effects of TAPI-2 on these ovulation-related processes. Gonadotropin-induced phosphorylation of ERK1/2 was also inhibited in rat granulosa cells treated with TAPI-2 or after transfection with Tace/Adam17 small interfering RNA. Induced expression of Tnfaip6 mRNA was also reduced by Tace/Adam17 small interfering RNA. Thus, TACE/ADAM17 is induced and the activity is involved in porcine COC expansion as well as oocyte meiotic maturation through the activation of EGF receptor in cumulus cells.

scholarly journals Epidermal growth factor receptor downregulation in cultured bovine cumulus cells: reconstitution of calcium signaling and stimulated membrane permeabilization

Reproduction ◽  
2005 ◽  
Vol 130 (4) ◽  
pp. 517-528 ◽  
Author(s):  
Zhong Zhao ◽  
Damien Garbett ◽  
Julia L Hill ◽  
David J Gross
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Cumulus Cell ◽  
Growth Factor Receptor ◽  
Cumulus Cells ◽  
Membrane Permeabilization ◽  
Egf Receptors ◽  
Epidermal Growth

Cumulus cell–oocyte complexes (COCs), culturedin vitro, are competent for maturation and fertilization. Inclusion of epidermal growth factor (EGF) in the COC culture medium enhancesin vitromaturation and subsequent embryonic development. It has been shown that isolated COCs exposed to EGF respond with a prolonged and pulsatile release of Ca2+into the extra-cellular medium and that cumulus cells (CCs) of complexes exhibit both a slow rise in intracellular [Ca2+] ([Ca2+]i) and plasma membrane permeabilization in response to EGF. These unusual signaling responses were examined in isolated, cultured bovine CCs. Few individual CCs showed [Ca2+]iincreases; the lack of response was found to be due to decrease of expression of endogenous EGF receptors after dissociation. CCs transfected with a human EGF receptor–GFP fusion protein showed robust, prolonged, EGF-stimulated [Ca2+]ielevations characteristic of CC responses in intact COCs. Many CCs that responded to EGF stimulation with a [Ca2+]irise also released entrapped fura-2 dye at the peak of the [Ca2+]iresponse, suggesting that CC permeabilization and death follows activation of the EGF receptor. The [Ca2+]ielevation due to EGF stimulation and subsequent membrane permeabilization was shown to be mediated by the inositol triphosphate signaling pathway.

scholarly journals Paracrine and Autocrine Regulation of Epidermal Growth Factor-Like Factors in Cumulus Oocyte Complexes and Granulosa Cells: Key Roles for Prostaglandin Synthase 2 and Progesterone Receptor

2006 ◽  
Vol 20 (6) ◽  
pp. 1352-1365 ◽  
Author(s):  
Masayuki Shimada ◽  
Inmaculada Hernandez-Gonzalez ◽  
Ignacio Gonzalez-Robayna ◽  
JoAnne S. Richards
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Progesterone Receptor ◽  
Granulosa Cells ◽  
Egf Receptor ◽  
Immune Cell ◽  
Cumulus Cells ◽  
Functional Changes ◽  
Prostaglandin Synthase ◽  
Epidermal Growth

Abstract The molecular bridges that link the LH surge with functional changes in cumulus cells that possess few LH receptors are being unraveled. Herein we document that epidermal growth factor (EGF)-like factors amphiregulin (Areg), epiregulin (Ereg), and betacellulin (Btc) are induced in cumulus oocyte complexes (COCs) by autocrine and paracrine mechanisms that involve the actions of prostaglandins (PGs) and progesterone receptor (PGR). Areg and Ereg mRNA and protein levels were reduced significantly in COCs and ovaries collected from prostaglandin synthase 2 (Ptgs2) null mice and Pgr null (PRKO) mice at 4 h and 8 h after human chorionic gonadotropin, respectively. In cultured COCs, FSH/forskolin induced Areg mRNA within 0.5 h that peaked at 4 h, a process blocked by inhibitors of p38MAPK (SB203580), MAPK kinase (MEK) 1 (PD98059), and PTGS2 (NS398) but not protein kinase A (PKA) (KT5720). Conversely, AREG but not FSH induced Ptsg2 mRNA at 0.5 h with peak expression of Ptgs2 and Areg mRNAs at 4 h, processes blocked by the EGF receptor tyrosine kinase inhibitor AG1478 (AG), PD98059, and NS398. PGE2 reversed the inhibitory effects of AG on AREG-induced expression of Areg but not Ptgs2, placing Ptgs2 downstream of EGF-R signaling. Phorbol 12-myristate 13-acetate (PMA) and adenovirally expressed PGRA synergistically induced Areg mRNA in granulosa cells. In COCs, AREG not only induced genes that impact matrix formation but also genes involved in steroidogenesis (StAR, Cyp11a1) and immune cell-like functions (Pdcd1, Runx1, Cd52). Collectively, FSH-mediated induction of Areg mRNA via p38MAPK precedes AREG induction of Ptgs2 mRNA via ERK1/2. PGs acting via PTGER2 in cumulus cells provide a secondary, autocrine pathway to regulate expression of Areg in COCs showing critical functional links between G protein-coupled receptor and growth factor receptor pathways in ovulating follicles.

scholarly journals Epidermal Growth Factor Stimulates Human Trophoblast Cell Migration through Rho A and Rho C Activation

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1732-1742 ◽  
Author(s):  
Jian Han ◽  
Li Li ◽  
Jiongyu Hu ◽  
Lili Yu ◽  
Yingru Zheng ◽  
...  
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Actin Cytoskeleton ◽  
Small Interfering Rna ◽  
Trophoblast Cell ◽  
C3 Exoenzyme ◽  
Epidermal Growth ◽  
Interfering Rna ◽  
Trophoblast Migration

This study investigated the roles of Rho protein in epidermal growth factor (EGF)-induced trophoblast cell migration and its mechanism. Using choriocarcinoma cell lines JEG-3 and JAR and first-trimester human chorionic villus explant cultures on matrigel, we examined EGF-mediated stimulation of trophoblast migration. EGF is shown to have a dose-dependent effect on trophoblast migration. A low concentration of EGF (1 ng/ml) has a stimulatory effect on cell migration, whereas high concentrations of EGF (100 ng/ml) shows an inhibitory effect. EGF (1 ng/ml) activates RhoA and RhoC, but not RhoB, through elevated protein levels and activity. EGF-induced migration was shown to be inhibited by either cell-permeable C3 exoenzyme transferase or selective RhoA or RhoC small interfering RNAs. The inhibition was not mitigated by the addition of EGF, suggesting that RhoA and RhoC play an important role in trophoblast migration and are obligatory for EGF action. Treatment of JEG-3 and JAR cells with RhoA small interfering RNA induced F-actin cytoskeleton disruption and cell shrinkage, which is consistent with the effect of C3 exoenzyme transferase, and this action was not mitigated by EGF treatment. RhoC small interfering RNA had no apparent effect on the F-actin arrangement, suggesting that RhoA but not RhoC takes part in the EGF-induced migration through F-actin rearrangement. These results indicate that RhoA and RhoC play more important roles than RhoB in EGF-mediated migration of trophoblast cells, and RhoA but not RhoC regulates this migration through F-actin cytoskeleton reorganization.

scholarly journals Epidermal Growth Factor Family Members: Endogenous Mediators of the Ovulatory Response

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 77-84 ◽  
Author(s):  
H. Ashkenazi ◽  
X. Cao ◽  
S. Motola ◽  
M. Popliker ◽  
M. Conti ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Oocyte Maturation ◽  
Egf Receptor ◽  
Kinase Inhibitor ◽  
Meiotic Maturation ◽  
Expression Of Genes ◽  
Epidermal Growth ◽  
Stimulation Of

Previous studies showed that epidermal growth factor (EGF) and TGFα mimic the action of LH on the resumption of oocyte maturation. We tested whether EGF-like agents, such as amphiregulin (AR), epiregulin (ER), and betacellulin (BTC), also mediate the LH stimulation of the ovulatory response in the rat. LH induced transient follicular expression of AR, ER, and BTC mRNA, reaching a maximum after 3-h incubation. Furthermore, the addition of ER, AR, and BTC to the culture medium could mimic some of LH actions. AR and ER fully simulated LH-induced resumption of meiosis in vitro, whereas BTC was less effective. To study the putative involvement of EGF-like factors in mediation of LH signal, the effect of the EGF receptor kinase inhibitor AG1478 was tested. When added with LH, AG1478, but not its inactive analog AG43, reduced EGF receptor phosphorylation and oocyte maturation compared with follicles treated with LH only. In addition to the inhibition of resumption of meiosis, AG1478 administration into the bursa (3 μg/bursa) resulted in 51% (P < 0.0005) inhibition of ovulation in the treated ovaries, compared with the untreated contralateral ones, as well as to the vehicle-treated ovaries (P < 0.02). LH, as well as ER, induced the expression of genes associated with the ovulatory response like rat hyaluronan synthase-2, cycloxygenase-2, and TNFα-stimulated gene 6 mRNA, whereas AG1478 inhibited this effect of LH. Release of EGF-like factors from the membrane is dependent on activated metalloproteases. Indeed, Galardin, a broad-spectrum metalloprotease inhibitor, but not a specific matrix metalloprotease 2 and 9 inhibitor, suppressed meiotic maturation induced by LH. Conversely, meiotic maturation induced by ER was not affected by Galardin, thus, supporting the notion that LH releases follicular membrane-bound EGF-like agents. In summary, EGF-like factors such as ER, AR, and BTC seem to mediate, at least partially, the LH stimulation of oocyte maturation, ovulatory enzyme expression, and ovulation.

scholarly journals Epidermal Growth Factor Receptor Signaling-Dependent Calcium Elevation in Cumulus Cells Is Required for NPR2 Inhibition and Meiotic Resumption in Mouse Oocytes

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3401-3409 ◽  
Author(s):  
Yakun Wang ◽  
Nana Kong ◽  
Na Li ◽  
Xiaoqiong Hao ◽  
Kaiwen Wei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Natriuretic Peptide ◽  
Oocyte Maturation ◽  
Guanylyl Cyclase ◽  
Egf Receptor ◽  
Cumulus Cells ◽  
Receptor Signaling ◽  
Epidermal Growth ◽  
Guanylyl Cyclase Activity

In preovulatory ovarian follicles, the oocyte is maintained in meiotic prophase arrest by natriuretic peptide precursor C (NPPC) and its receptor natriuretic peptide receptor 2 (NPR2). LH treatment results in the decrease of NPR2 guanylyl cyclase activity that promotes resumption of meiosis. We investigated the regulatory mechanism of LH-activated epidermal growth factor (EGF) receptor signaling on NPR2 function. Cumulus cell-oocyte complex is cultured in the medium with 30 nM NPPC to prevent oocyte spontaneous maturation. In this system, EGF could stimulate oocyte meiotic resumption after 4 hours of incubation. Further study showed that EGF elevated intracellular calcium concentrations of cumulus cells and decreased cGMP levels in cumulus cells and oocytes, and calcium-elevating reagents ionomycin and sphingosine-1-phosphate mimicked the effects of EGF on oocyte maturation and cGMP levels. EGF-mediated cGMP levels and meiotic resumption could be reversed by EGF receptor inhibitor AG1478 and the calcium chelator bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid, tetra(acetoxymethyl)-ester. EGF also decreased the expression of Npr2 mRNA in cumulus cells, which may not be involved in meiotic resumption, because the block of NPR2 protein de novo synthesis by cycloheximide had no effect on NPPC and EGF-mediated oocyte maturation. However, EGF had no effect on oocyte maturation when meiotic arrest was maintained in the present of cGMP analog 8-bromoadenosine-cGMP. These results suggest that EGF receptor signaling induces meiotic resumption by elevating calcium concentrations of cumulus cells to decrease NPR2 guanylyl cyclase activity.

Epidermal growth factor receptor targeted methotrexate and small interfering RNA co-delivery

2018 ◽  
Vol 20 (7-8) ◽  
pp. e3041 ◽  
Author(s):  
Benjamin Steinborn ◽  
Ines Truebenbach ◽  
Stephan Morys ◽  
Ulrich Lächelt ◽  
Ernst Wagner ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Small Interfering Rna ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Interfering Rna

947: Chemopreventive Effects of COX-2 Inhibitor and Epidermal Growth Factor (EGF)-Receptor Kinase Inhibitor on Rat Urinary Bladder Tumorigenesis

2004 ◽  
Vol 171 (4S) ◽  
pp. 251-251
Author(s):  
Kazunori Hattori ◽  
Katsuyuki Iida ◽  
Akira Johraku ◽  
Sadamu Tsukamoto ◽  
Taeko Asano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Urinary Bladder ◽  
Egf Receptor ◽  
Kinase Inhibitor ◽  
Receptor Kinase ◽  
Rat Urinary Bladder ◽  
Epidermal Growth ◽  
Cox 2
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