The Experts below are selected from a list of 225 Experts worldwide ranked by ideXlab platform

Vincent Giguere - One of the best experts on this subject based on the ideXlab platform.

  • diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor err beta
    Genes & Development, 2001
    Co-Authors: Gilles Tremblay, Tilo Kunath, Denis Bergeron, Line Lapointe, Celine Champigny, Joann Bader, Janet Rossant, Vincent Giguere
    Abstract:

    The orphan nuclear receptor ERR beta is expressed in undifferentiated trophoblast stem cell lines and extraembryonic ectoderm, and genetic ablation of ERR beta results in abnormal trophoblast proliferation and precocious differentiation toward the giant cell lineage. Here, we show that the synthetic estrogen diethylstilbestrol (DES) promotes coactivator release from ERR beta and inhibits its transcriptional activity. Strikingly, treatment of trophoblast stem cells with DES led to their differentiation toward the polyploid giant cell lineage. In addition, DES-treated pregnant mice exhibited abnormal early Placenta Development associated with an overabundance of trophoblast giant cells and an absence of diploid trophoblast. These results define a novel pathway for DES action and provide evidence for steroidlike control of trophoblast Development.

  • orphan nuclear receptors from gene to function
    Endocrine Reviews, 1999
    Co-Authors: Vincent Giguere
    Abstract:

    I. Introduction II. Nuclear Receptors: General Concepts A. Anatomy of nuclear receptors B. Mechanisms of action III. Orphan Nuclear Receptors A. Definition B. Nomenclature C. Structural and functional diversity IV. Novel Hormone Response Systems: RXR and Its Heterodimeric Partners A. RXR: rexinoids B. PPAR: multiple ligands, multiple functions C. PXR: pregnanes, xenobiotic compounds, and benzoate derivatives D. CAR (constitutive androstane receptor): androstanes and phenobarbital E. LXR: control of cholesterol metabolism by oxysterols F. FXR: bile acids receptor V. Orphans in Search of a Home A. HNF4: diabetes and possible regulation by acyl-coenzyme A (CoA) thioesters B. FTZ-F1: steroidogenesis and sexual Development C. Rev-Erb: singular members of the superfamily D. ROR: neuron Development and T cell selection E. TR2: the testis receptors F. TLX: forebrain Development G. COUP-TF: neurogenesis, angiogenesis, and heart Development H. ERR: Placenta Development and control of lipid metabolism I. NGFI-B: hyp...

Xiaowei Zhu - One of the best experts on this subject based on the ideXlab platform.

  • genome amplification and cellular senescence are hallmarks of human Placenta Development
    PLOS Genetics, 2018
    Co-Authors: Philipp Velicky, Gudrun Meinhardt, Kerstin Plessl, Sigrid Vondra, Tamara Weiss, Peter Haslinger, Thomas Lendl, Karin Aumayr, Mario Mairhofer, Xiaowei Zhu
    Abstract:

    Genome amplification and cellular senescence are commonly associated with pathological processes. While physiological roles for polyploidization and senescence have been described in mouse Development, controversy exists over their significance in humans. Here, we describe tetraploidization and senescence as phenomena of normal human Placenta Development. During pregnancy, Placental extravillous trophoblasts (EVTs) invade the pregnant endometrium, termed decidua, to establish an adapted microenvironment required for the developing embryo. This process is critically dependent on continuous cell proliferation and differentiation, which is thought to follow the classical model of cell cycle arrest prior to terminal differentiation. Strikingly, flow cytometry and DNAseq revealed that EVT formation is accompanied with a genome-wide polyploidization, independent of mitotic cycles. DNA replication in these cells was analysed by a fluorescent cell-cycle indicator reporter system, cell cycle marker expression and EdU incorporation. Upon invasion into the decidua, EVTs widely lose their replicative potential and enter a senescent state characterized by high senescence-associated (SA) β-galactosidase activity, induction of a SA secretory phenotype as well as typical metabolic alterations. Furthermore, we show that the shift from endocycle-dependent genome amplification to growth arrest is disturbed in androgenic complete hydatidiform moles (CHM), a hyperplastic pregnancy disorder associated with increased risk of developing choriocarinoma. Senescence is decreased in CHM-EVTs, accompanied by exacerbated endoreduplication and hyperploidy. We propose induction of cellular senescence as a ploidy-limiting mechanism during normal human Placentation and unravel a link between excessive polyploidization and reduced senescence in CHM.

Douglas A Kniss - One of the best experts on this subject based on the ideXlab platform.

Ishing Yu - One of the best experts on this subject based on the ideXlab platform.

  • lack of thromboxane synthase prevents hypertension and fetal growth restriction after high salt treatment during pregnancy
    PLOS ONE, 2016
    Co-Authors: Chiepein Chen, Ishing Yu
    Abstract:

    Preeclampsia (PE) is a potentially fatal pregnancy-related hypertensive disorder characterized by poor Placenta Development that can cause fetal growth restriction. PE-associated pathologies, including thrombosis, hypertension, and impaired Placental Development, may result from imbalances between thromboxane A2 (TXA2) and prostacyclin. Low-dose aspirin, which selectively inhibits TXA2 production, is used to prevent high-risk PE. However, the role of TXA2 in aspirin-mediated protective effects in women with PE is not understood fully. In this study, we examined the role of prostanoids in PE using human samples and an induced PE mouse model. We demonstrated that the administration of salted drinking water (2.7% NaCl) to wild-type mice resulted in elevated Placental TXA2 synthase (TXAS) and plasma TXA2, but not prostacyclin, levels, which was also found in our clinical PE Placenta samples. The high salt-treated wild-type pregnant mice had shown unchanged maternal body weight, hypertension (MAP increase 15 mmHg), and decreased pup weight (~50%) and size (~24%), but these adverse effects were ameliorated in TXAS knockout (KO) mice. Moreover, increased expression of interleukin-1β and downstream phosphorylated-p38-mitogen-activated protein kinase were concordant with apoptosis induction in the Placentas of salt water-treated wild-type mice. These alterations were not observed in TXAS KO mice. Together, our data suggest that TXA2 depletion has anti-PE effects due to the prevention of hypertension and Placental damage through downregulation of the interleukin-1β pathway.

Xinggang Wang - One of the best experts on this subject based on the ideXlab platform.

  • hectd1 modulates centrosome duplication cytokinesis and ciliogenesis through hax1
    2018
    Co-Authors: Xinggang Wang
    Abstract:

    HECTD1, also known as E3 ubiquitin ligase with affinity to the inhibin receptor (EULIR), has been demonstrated to play a critical role in embryonic Development. When HECTD1 mutated, neural tube closure defects occur and Placenta Development is hampered. Ongoing research demonstrated the many involvements of HECTD1 in cell spreading, cell migration and in Wnt signaling transduction. Defect of HECTD1 accelerates cell spreading/migration and invasion through inhibiting IQGAP1 degradation and excess Hsp90 secretion. HECTD1 ubiquitylates adenomatous polyposis coli (APC), and promotes APC/Axin interaction, which negatively regulates the Wnt signaling pathway. Although all these functions of HECTD1 have already been reported elsewhere, many other functions of HECTD1 remain unknown. The involvement of HECTD1 in mitosis and cytokinesis was noticed in my previous research. Immunofluorescence staining of HECTD1 in different cell lines demonstrated that HECTD1 is localized at different subcellular sites, such as the centrosome, the basal body of cilia, the intercellular bridge, cytoplasm and in the nucleus. These findings promoted me to further investigate into the function of HECTD1 in the centrosome, in ciliogenesis and in cytokinesis. First, by using HECTD1 mutated (HECTD1r/r) mouse embryonic fibroblasts (MEF) and HECTD1 short-hairpin RNA (shRNA) down-regulated HeLa cells, centrosome numbers were examined. The results revealed that loss of HECTD1 induced centrosome over-duplication. Centrosome abbreviations sequentially affect ciliogenesis both in HECTD1r/r and HECTD1-KD cells. To study the mechanism how HECTD1 controls centrosome numbers, I studied the relationship of HECTD1 with its interacting partners. HAX1 (HCLS1-associated protein X1), one of HECTD1 interacting partners previously screened by yeast two-hybrid assay, was regulated through HECTD1 ubiquitination. HAX1 is also located in the centrosome and becomes accumulated in centrosome during the S phase of the cell cycle when HECTD1 is down-regulated. Over-expression HAX1 phenocopied centrosome over-duplication as cells with defected HECTD1. Furthermore, by knockdown of HAX1, HECTD1-induced over-duplication of the centrosomes was abolished. HAX1 works as a scaffold protein to recruit proteins of the Hippo pathway, SAV1 and MOB1a, to the centrosome in order to control centrosome duplication. Thus, we propose the HECTD1-HAX1-SAV1-MOB1a axis to control centrosome duplication numbers. Besides amplification of the centrosome and impaired ciliogenesis, defects in the completion of cytokinesis were also found in HECTD1-KD cells. Down-regulation of HECTD1 resulted in elongation of intercellular bridges and missed abscission. HAX1 formed ring structure in the midbody and its ectopic expression resulted in similar defects as in HECTD1-KD cells. Knocdown of HECTD1 or ectopic localization of HAX1 resulted in mislocalization of microtubules binding proteins, such as MKLP1 (Mitotic kinesin-like protein), PRC1 (Protein required for cytokinesis) and Kif4 in the midbody. Depletion of HAX1 could partly rescue the defects in cytokinesis caused by knockdown of HECTD1, by shortening the length of the intercellular bridges, while the abscission site assembly was recovered with Plk1 inhibitor, BI2536. Finally, to further investigate the function of HECTD1 cell cycle regulation, epidermal growth factor (EGF) was employed. The EGF/EGF receptor (EGFR) endocytic and signaling pathways were explored. Knockdown of HECTD1 inhibited the degradation of EGFR and promoted the recycling of EGF/EGFR through APPL1/Rab4. Furthermore, knockdown of HECTD1 sustained phosphorylated Akt and MAPK protein expression after EGF stimulation, without increasing cell proliferation rates. In addition, SNAIL, the key regulator of epithelial-mesenchymal transition (EMT), protein expression was significantly increased in HECTD1-KD cells. SNAIL and HECTD1 protein-protein interaction was determined with immunoprecipitation. Cell morphology and EMT associated protein expression levels changed between control and HECTD1-KD cells, consistent with the notion that mutations in the HECTD1 gene are detected in various human cancers. This finding implies that HECTD1 may be involved in the metastasis of cancer and may be associated with clinical outcome of cancer. Taken all these findings together, HECTD1 is multi-functional protein depending on its substrates, controlling centrosome duplication, ciliogenesis, and cytokinesis through HAX1, determining the EGFR trafficking from sorting endosome to early or recycling endosome via APPL1, and interacting with SNAIL modulating EMT.

  • hectd1 modulates centrosome duplication cytokinesis and ciliogenesis through hax1
    2018
    Co-Authors: Xinggang Wang
    Abstract:

    HECTD1, also known as E3 ubiquitin ligase with affinity to the inhibin receptor (EULIR), has been demonstrated to play a critical role in embryonic Development. When HECTD1 mutated, neural tube closure defects occur and Placenta Development is hampered. Ongoing research demonstrated the many involvements of HECTD1 in cell spreading, cell migration and in Wnt signaling transduction. Defect of HECTD1 accelerates cell spreading/migration and invasion through inhibiting IQGAP1 degradation and excess Hsp90 secretion. HECTD1 ubiquitylates adenomatous polyposis coli (APC), and promotes APC/Axin interaction, which negatively regulates the Wnt signaling pathway. Although all these functions of HECTD1 have already been reported elsewhere, many other functions of HECTD1 remain unknown. The involvement of HECTD1 in mitosis and cytokinesis was noticed in my previous research. Immunofluorescence staining of HECTD1 in different cell lines demonstrated that HECTD1 is localized at different subcellular sites, such as the centrosome, the basal body of cilia, the intercellular bridge, cytoplasm and in the nucleus. These findings promoted me to further investigate into the function of HECTD1 in the centrosome, in ciliogenesis and in cytokinesis. First, by using HECTD1 mutated (HECTD1r/r) mouse embryonic fibroblasts (MEF) and HECTD1 short-hairpin RNA (shRNA) down-regulated HeLa cells, centrosome numbers were examined. The results revealed that loss of HECTD1 induced centrosome over-duplication. Centrosome abbreviations sequentially affect ciliogenesis both in HECTD1r/r and HECTD1-KD cells. To study the mechanism how HECTD1 controls centrosome numbers, I studied the relationship of HECTD1 with its interacting partners. HAX1 (HCLS1-associated protein X1), one of HECTD1 interacting partners previously screened by yeast two-hybrid assay, was regulated through HECTD1 ubiquitination. HAX1 is also located in the centrosome and becomes accumulated in centrosome during the S phase of the cell cycle when HECTD1 is down-regulated. Over-expression HAX1 phenocopied centrosome over-duplication as cells with defected HECTD1. Furthermore, by knockdown of HAX1, HECTD1-induced over-duplication of the centrosomes was abolished. HAX1 works as a scaffold protein to recruit proteins of the Hippo pathway, SAV1 and MOB1a, to the centrosome in order to control centrosome duplication. Thus, we propose the HECTD1-HAX1-SAV1-MOB1a axis to control centrosome duplication numbers. Besides amplification of the centrosome and impaired ciliogenesis, defects in the completion of cytokinesis were also found in HECTD1-KD cells. Down-regulation of HECTD1 resulted in elongation of intercellular bridges and missed abscission. HAX1 formed ring structure in the midbody and its ectopic expression resulted in similar defects as in HECTD1-KD cells. Knocdown of HECTD1 or ectopic localization of HAX1 resulted in mislocalization of microtubules binding proteins, such as MKLP1 (Mitotic kinesin-like protein), PRC1 (Protein required for cytokinesis) and Kif4 in the midbody. Depletion of HAX1 could partly rescue the defects in cytokinesis caused by knockdown of HECTD1, by shortening the length of the intercellular bridges, while the abscission site assembly was recovered with Plk1 inhibitor, BI2536. Finally, to further investigate the function of HECTD1 cell cycle regulation, epidermal growth factor (EGF) was employed. The EGF/EGF receptor (EGFR) endocytic and signaling pathways were explored. Knockdown of HECTD1 inhibited the degradation of EGFR and promoted the recycling of EGF/EGFR through APPL1/Rab4. Furthermore, knockdown of HECTD1 sustained phosphorylated Akt and MAPK protein expression after EGF stimulation, without increasing cell proliferation rates. In addition, SNAIL, the key regulator of epithelial-mesenchymal transition (EMT), protein expression was significantly increased in HECTD1-KD cells. SNAIL and HECTD1 protein-protein interaction was determined with immunoprecipitation. Cell morphology and EMT associated protein expression levels changed between control and HECTD1-KD cells, consistent with the notion that mutations in the HECTD1 gene are detected in various human cancers. This finding implies that HECTD1 may be involved in the metastasis of cancer and may be associated with clinical outcome of cancer. Taken all these findings together, HECTD1 is multi-functional protein depending on its substrates, controlling centrosome duplication, ciliogenesis, and cytokinesis through HAX1, determining the EGFR trafficking from sorting endosome to early or recycling endosome via APPL1, and interacting with SNAIL modulating EMT.