Prostaglandin E2-Mediated Migration of Human Trophoblast Requires RAC1 and CDC421

Nicola, Catalin; Lala, Peeyush K.; Chakraborty, Chandan

doi:10.1095/biolreprod.107.065433

Cited by 47 publications

(33 citation statements)

References 64 publications

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“…It is notable that knockdown of both Cdc42 and Rac1 is necessary to completely abolish the response to leucine deprivation. Similar data have been reported for other models (17,62). For example, epidermal growth factor activates both Rac1 and Cdc42 in a synergistic manner to regulate the downstream pathway (50).…”

Section: Discussionsupporting

confidence: 86%

Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

Chaveroux

Jousse

Chérasse

et al. 2009

Molecular and Cellular Biology

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It has been well established that amino acid availability can control gene expression. Previous studies have shown that amino acid depletion induces transcription of the ATF3 (activation transcription factor 3) gene through an amino acid response element (AARE) located in its promoter. This event requires phosphorylation of activating transcription factor 2 (ATF2), a constitutive AARE-bound factor. To identify the signaling cascade leading to phosphorylation of ATF2 in response to amino acid starvation, we used an individual gene knockdown approach by small interfering RNA transfection. We identified the mitogen-activated protein kinase (MAPK) module MEKK1/MKK7/JNK2 as the pathway responsible for ATF2 phosphorylation on the threonine 69 (Thr69) and Thr71 residues. Then, we progressed backwards up the signal transduction pathway and showed that the GTPase Rac1/Cdc42 and the protein G␣12 control the MAPK module, ATF2 phosphorylation, and AARE-dependent transcription. Taken together, our data reveal a new signaling pathway activated by amino acid starvation leading to ATF2 phosphorylation and subsequently positively affecting the transcription of amino acid-regulated genes.

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Section: Discussionsupporting

confidence: 86%

Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

Chaveroux

Jousse

Chérasse

et al. 2009

Molecular and Cellular Biology

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“…Compared to normal pregnancy tissues, our research discovered that Rac1 expression declined in preeclampsia placental tissues. This evidence, along with the previous observation that Rac1 activity was significantly lower in women with preeclampsia and HELLP [6][7][8], supports the view that Rac1 potentially contributes to placental development. Furthermore, the present study showed the activity of Rac1 at different gestational stages and under preeclampsia conditions; these changes corresponded with the down-regulation of trophoblast invasion, suggesting that Rac1 may be involved in the regulation of trophoblast invasion to prevent shallow placental implantation.…”

Section: Discussionsupporting

confidence: 85%

“…Studies have also shown that the activity of Rac1 is downregulated in preeclampsia and HELLP syndrome [6], suggesting a potential contribution of Rac1 to placental development. Moreover, the activation of PTGER1 and PTGER4 which serve as mediators of the PGE 2 -induced migration of first trimester human EVTs can activate Rac1 [7]. A recent study indicated that RhoGDI2, which belongs to a family of Rho guanosine diphosphate dissociation inhibitors, suppressed EVT migration by inhibiting the activation of Rac1 [8].…”

Section: Rac1/β-catenin Signalling Pathway Contributes To Trophoblastmentioning

confidence: 99%

Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9

Fan

Hong

et al. 2016

Cell Physiol Biochem

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Background/Aims: Preeclampsia is an idiopathic and serious complication during gestation in which placental trophoblast cells differentiate into several functional subtypes, including highly invasive extravillous trophoblasts (EVTs). Although the cause and pathogenesis of preeclampsia have remained unclear, numerous studies have suggested that the inadequacy of EVT invasion leads to imperfect uterine spiral artery remodelling, which plays a crucial role in the development of preeclampsia. Rac1, or Ras-related C3 botulinum toxin substrate 1, was found to be a key regulator of the migration, invasion uand apoptosis of various tumour cells. Because EVTs share similar invasive and migratory biological behaviours with malignant cells, this study aimed to determine whether the Rac1 signalling pathway affects trophoblast invasion and is thus involved in the pathogenesis of preeclampsia. Methods: We measured the activity of Rac1 and its downstream targets, β-catenin, Snail and MMP9 in placental tissues from patients experiencing a normal pregnancy and those with preeclampsia. Furthermore, we treated HTR-8/SVneo cells with a shRNA Rac1 vector and the β-catenin inhibitor IWP-2 and explored Rac1 signalling pathway activation as well as the effects of Snail and β-catenin on trophoblast invasion. Results: In placental samples from patients experiencing a normal pregnancy and those with preeclampsia, active Rac1 levels and MMP9 protein and mRNA levels were significantly decreased in term pregnancy samples compared to early pregnancy samples. Lower levels were found in preeclampsia samples than in normal term pregnancy samples, and these levels significantly declined in severe preeclampsia samples compared with mild preeclampsia samples. Further analyses demonstrated that both Rac1 shRNA and the β-catenin inhibitor significantly suppressed MMP9 and Snail activation in trophoblasts, thus impairing trophoblast invasion. Notably, silencing Rac1 down-regulated the expression of β-catenin in HTR-8/SVneo cells, demonstrating that β-catenin is a downstream effector of Rac1 in trophoblast invasion. Conclusion: Our data suggest that Rac1-mediated activation of β-catenin might regulate Snail and MMP9 expression subsequently promoting trophoblast invasion in pregnancy.

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“…Note that SMAD genes belong to both the Wnt and the TGFβ signaling pathways. Interestingly, RAC1 was reported to regulate several reproductive events, including embryo implantation (Grewal et al, 2008;Nicola et al, 2008), meiotic spindle stability and anchoring in mammalian oocytes (Halet and Carroll, 2007), and embryonic epithelial morphogenesis (He et al, 2010). In addition, RAC1 can stimulate STAT3 activation and therefore affect the transcription of many genes (Faruqi et al, 2001;Park et al, 2004;Kawashima et al, 2006).…”

Section: Pituitary Gland Genes: Differentially Expressed and Interactingmentioning

confidence: 99%

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

Nguyen¹,

Reverter²,

Cánovas³

et al. 2017

Journal of Animal Science

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ABSTRACT:To understand genes, pathways, and networks related to puberty, we characterized the transcriptome of two tissues: the pituitary gland and ovaries. Samples were harvested from pre-and postpubertal Brahman heifers (same age group). Brahman heifers (Bos indicus) are older at puberty compared with Bos taurus, a productivity issue. With RNA sequencing, we identified differentially expressed (DEx) genes and important transcription factors (TF) and predicted coexpression networks. The number of DEx genes detected in the pituitary gland was 284 (P < 0.05), and VWC2L was the most DEx gene (fold change = 4.12, P = 0.01). The gene VWC2L promotes bone mineralization through transforming growth factor-β (TGFβ) signaling. Further studies of the link between bone mineralization and puberty could target VWC2L. In ovaries, 3,871 genes were DEx (P < 0.05). Four highly DEx genes were noteworthy for their function: SLC6A13 (a γ-aminobutyric acid [GABA] transporter), OXT (oxytocin), and NPY (neuropeptide Y) and its receptor NPY2R. These genes had higher ovarian expression in postpubertal heifers. The GABA and its receptors and transporters were expressed in the ovaries of many mammals, suggesting a role for this pathway beyond the brain. The OXT pathway has been known to influence the timing of puberty in rats, via modulation of GnRH. The effects of NPY at the hypothalamus, pituitary gland, and ovaries have been documented. Neuropeptide Y and its receptors are known factors in the release of GnRH, similar to OXT and GABA, although their roles in ovarian tissue are less clear. Pathways previously related to puberty such as TGFβ signaling (P = 6.71 × 10 −5 ), Wnt signaling (P = 4.1 × 10 −2 ), and peroxisome proliferator-activated receptor (PPAR) signaling (P = 4.84 × 10 −2 ) were enriched in our data set. Seven genes were identified as key TF in both tissues: HIC2, ZIC4, ZNF219, ZSCAN26, LHX1, OLIG1, and a novel gene. An ovarian subnetwork created with TF and significant ovarian DEx genes revealed five zinc fingers as regulators: ZNF507, ZNF12, ZNF512, ZNF184, and ZNF432. Recent work of hypothalamic gene expression also pointed to zinc fingers as TF for bovine puberty. Although some zinc fingers may be ubiquitously expressed, the identification of DEx genes in common across tissues points to key regulators of puberty. The hypothalamus and pituitary gland had eight DEx genes in common. The hypothalamus and ovaries had 89 DEx genes in common. The pituitary gland and ovaries had 48 DEx genes in common. Our study confirmed the complexity of puberty and suggested further investigation on genes that code zinc fingers.

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Prostaglandin E2-Mediated Migration of Human Trophoblast Requires RAC1 and CDC421

Cited by 47 publications

References 64 publications

Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

Identification of a Novel Amino Acid Response Pathway Triggering ATF2 Phosphorylation in Mammals

Rac1/β-Catenin Signalling Pathway Contributes to Trophoblast Cell Invasion by Targeting Snail and MMP9

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

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