Prostaglandin E<sub>2</sub> maintains mouse ESC undifferentiated state through regulation of connexin31, connexin43 and connexin45 expression: Involvement of glycogen synthase kinase 3β/β‐catenin

Yun, Seung Pil; Ryu, Jung Min; Park, Jae Hong; Kim, Miok; Lee, Jang Hern; Han, Ho Jae

doi:10.1111/boc.201100032

Cited by 12 publications

(8 citation statements)

References 32 publications

(42 reference statements)

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“…The rat Cx43 promoter contains several sequences resembling half the palindromic estrogen response elements (half-EREs), which are functional when co-transfected with estrogen receptor cDNA into HeLa cells [29]. In addition, it has been demonstrated that estrogens in osteocyte and mouse embryonic stem cells, also bound to membrane ERα, induce activation of phosphatidylinositol 3-kinase (PI3K)/Akt, and that one of the tyrosine kinases, PI3K/Akt, participates in the up-regulation of Cx43 [30]–[31]. However, the effect of E 2 on GJIC in Leydig cells and their only gap-junctional connexin Cx43 has not been studied.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

Liu

Wang

et al. 2013

PLoS ONE

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BackgroundBesides androgens, estrogens produced in Leydig cells are also crucial for mammalian germ cell differentiation. Transforming growth factor-β1 (TGF-β1) is now known to have multiple effects on regulation of Leydig cell function. The objective of the present study is to determine whether TGF-β1 regulates estradiol (E2) synthesis in adult rat Leydig cells and then to assess the impact of TGF-β1 on Cx43-based gap junctional intercellular communication (GJIC) between Leydig cells.Methodology/Principal FindingsPrimary cultured Leydig cells were incubated in the presence of recombinant TGF-β1 and the production of E2 as well as testosterone (T) were measured by RIA. The activity of P450arom was addressed by the tritiated water release assay and the expression of Cyp19 gene was evaluated by Western blotting and real time RT-PCR. The expression of Cx43 and GJIC were investigated with immunofluorescence and fluorescence recovery after photo-bleaching (FRAP), respectively. Results from this study show that TGF-β1 down-regulates the level of E2 secretion and the activity of P450arom in a dose-dependent manner in adult Leydig cells. In addition, the expression of Cx43 and GJIC was closely related to the regulation of E2 and TGF-β1, and E2 treatment in turn restored the inhibition of TGF-β1 on GJIC.ConclusionsOur results indicate, for the first time in adult rat Leydig cells, that TGF-β1 suppresses P450arom activity, as well as the expression of the Cyp19 gene, and that depression of E2 secretion leads to down-regulation of Cx43-based GJIC between Leydig cells.

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Section: Introductionmentioning

confidence: 99%

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

Liu

Wang

et al. 2013

PLoS ONE

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“…Research with other cell types has confirmed that up-regulation of CX43 expression in response to WNT signaling occurs at the transcriptional level and involves an association of CTNNB1 with the promoter of the Gja1 gene encoding CX43 [11][12][13]19]. Given this evidence, it is likely that WNT2 influences CX43 expression and GJIC in granulosa cells in part by up-regulating Gja1 transcription through stabilization and nuclear translocation of CTNNB1.…”

Section: Discussionmentioning

confidence: 99%

The Canonical WNT2 Pathway and FSH Interact to Regulate Gap Junction Assembly in Mouse Granulosa Cells1

Wang

Gillio-Meina

Chen

et al. 2013

Biology of Reproduction

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WNTs are extracellular signaling molecules that exert their actions through receptors of the frizzled (FZD) family. Previous work indicated that WNT2 regulates cell proliferation in mouse granulosa cells acting through CTNNB1 (beta-catenin), a key component in canonical WNT signaling. In other cells, WNT signaling has been shown to regulate expression of connexin43 (CX43), a gap junction protein, as well as gap junction assembly. Since previous work demonstrated that CX43 is also essential in ovarian follicle development, the objective of this study was to determine if WNT2 regulates CX43 expression and/or gap-junctional intercellular communication (GJIC) in granulosa cells. WNT2 knockdown via siRNA markedly reduced CX43 expression and GJIC. CX43 expression, the extent of CX43-containing gap junction membrane, and GJIC were also reduced by CTNNB1 transient knockdown. CTNNB1 is mainly localized to the membranes between granulosa cells but disappeared from this location after WNT2 knockdown. Furthermore, CTNNB1 knockdown interfered with the ability of follicle-stimulating hormone (FSH) to promote the mobilization of CX43 into gap junctions. We propose that the WNT2/CTNNB1 pathway regulates CX43 expression and GJIC in granulosa cells by modulating CTNNB1 stability and localization in adherens junctions, and that this is essential for FSH stimulation of GJIC.

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“…Furthermore, short-term incubation (30 min) in the presence of 8Br-cAMP, 8Br-cGMP, BAY, or DADS had no effects on the Cx43 expression levels (data not shown). A number of reports have shown that increased cAMP increases Cx43 expression, functionality, and phosphorylation (Lampe and Lau, 2004) and specifically the increase in Cx43 expression appears to be mediated by PKA (Paulson et al, 2000) in hepatoma cells and it has only recently been reported that the cAMP/PKA pathway regulates GJIC in mouse embryonic stem cells (Yun et al, 2012). The stimulation of GJIC by 8Br-cAMP observed in this study was reversed by the PKC inhibitor CalC, and it was surprising to note that neither PKA nor PKG had any role in regulating 8Br-cAMP-stimulated GJIC.…”

Section: Discussionmentioning

confidence: 99%

Control of Vascular Smooth Muscle Cell Growth by Connexin 43

Joshi¹,

Martin²,

Shaver³

et al. 2012

Front. Physio.

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Connexin 43 (Cx43), the principal gap junction protein in vascular smooth muscle cells (VSMCs), regulates movement of ions and other signaling molecules through gap junction intercellular communication (GJIC) and plays important roles in maintaining normal vessel function; however, many of the signaling mechanisms controlling Cx43 in VSMCs are not clearly described. The goal of this study was to investigate mechanisms of Cx43 regulation with respect to VSMC proliferation. Treatment of rat primary VSMCs with the cAMP analog 8Br-cAMP, the soluble guanylate cyclase (sGC) stimulator BAY 41-2272 (BAY), or the Cx inducer diallyl disulfide (DADS) significantly reduced proliferation after 72 h compared with vehicle controls. Bromodeoxyuridine uptake revealed reduction (p < 0.05) in DNA synthesis after 6 h and flow cytometry showed reduced (40%) S-phase cell numbers after 16 h in DADS-treated cells compared with vehicle controls. Cx43 expression significantly increased after 270 min treatment with 8Br-cAMP, 8Br-cGMP, BAY or DADS. Inhibition of PKA, PKG or PKC reversed 8Br-cAMP-stimulated increases in Cx43 expression, whereas only PKG or PKC inhibition reversed 8Br-cGMP- and BAY-stimulated increases in total Cx43. Interestingly, stimulation of Cx43 expression by DADS was not dependent on PKA, PKG or PKC. Using fluorescence recovery after photobleaching, only 8Br-cAMP or DADS increased GJIC with 8Br-cAMP mediated by PKC and DADS mediated by PKG. Further, DADS significantly increased phosphorylation at MAPK-sensitive Serine (Ser)255 and Ser279, the cell cycle regulatory kinase-sensitive Ser262 and PKC-sensitive Ser368 after 30 min while 8Br-cAMP significantly increased phosphorylation only at Ser279 compared with controls. This study demonstrates that 8Br-cAMP- and DADS-enhanced GJIC rather than Cx43 expression and/or phosphorylation plays important roles in the regulation of VSMC proliferation and provides new insights into the growth-regulatory capacities of Cx43 in VSM.

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Prostaglandin E₂ maintains mouse ESC undifferentiated state through regulation of connexin31, connexin43 and connexin45 expression: Involvement of glycogen synthase kinase 3β/β‐catenin

Abstract: PGE₂ stimulates Cx isoforms via GSK-3β/β-catenin via EP2-receptor-dependent cAMP/PKA and PI3K/Akt in mouse ESCs, thereby partially contributing to the maintenance of their undifferentiated state.

Cited by 12 publications

References 32 publications

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

The Canonical WNT2 Pathway and FSH Interact to Regulate Gap Junction Assembly in Mouse Granulosa Cells1

Control of Vascular Smooth Muscle Cell Growth by Connexin 43

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Prostaglandin E2 maintains mouse ESC undifferentiated state through regulation of connexin31, connexin43 and connexin45 expression: Involvement of glycogen synthase kinase 3β/β‐catenin

Abstract: PGE₂ stimulates Cx isoforms via GSK-3β/β-catenin via EP2-receptor-dependent cAMP/PKA and PI3K/Akt in mouse ESCs, thereby partially contributing to the maintenance of their undifferentiated state.

Cited by 12 publications

References 32 publications

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

TGF-β1 Regulation of Estrogen Production in Mature Rat Leydig Cells

The Canonical WNT2 Pathway and FSH Interact to Regulate Gap Junction Assembly in Mouse Granulosa Cells1

Control of Vascular Smooth Muscle Cell Growth by Connexin 43

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Prostaglandin E₂ maintains mouse ESC undifferentiated state through regulation of connexin31, connexin43 and connexin45 expression: Involvement of glycogen synthase kinase 3β/β‐catenin