Molecular endocrinology最新文献_第2页

GnRH Stimulates Peptidylarginine Deiminase Catalyzed Histone Citrullination in Gonadotrope Cells. 促性腺激素刺激肽精氨酸脱亚胺酶催化组蛋白瓜氨酸化。

Molecular endocrinology Pub Date : 2016-10-01 Epub Date: 2016-09-07 DOI: 10.1210/me.2016-1085

Shaihla A Khan, Brian S Edwards, Aaron Muth, Paul R Thompson, Brian D Cherrington, Amy M Navratil

{"title":"GnRH Stimulates Peptidylarginine Deiminase Catalyzed Histone Citrullination in Gonadotrope Cells.","authors":"Shaihla A Khan, Brian S Edwards, Aaron Muth, Paul R Thompson, Brian D Cherrington, Amy M Navratil","doi":"10.1210/me.2016-1085","DOIUrl":"https://doi.org/10.1210/me.2016-1085","url":null,"abstract":"Peptidylarginine deiminase (PAD) enzymes convert histone tail arginine residues to citrulline resulting in chromatin decondensation. Our previous work found that PAD isoforms are expressed in female reproductive tissues in an estrous cycle-dependent fashion, but their role in the anterior pituitary gland is unknown. Thus, we investigated PAD expression and function in gonadotrope cells. The gonadotrope-derived LβT2 cell line strongly expresses PAD2 at the protein level compared with other PAD isoforms. Consistent with this, PAD2 protein expression is highest during the estrous phase of the estrous cycle and colocalizes with the LH β-subunit in the mouse pituitary. Using the GnRH agonist buserelin (GnRHa), studies in LβT2 and mouse primary gonadotrope cells revealed that 30 minutes of stimulation caused distinct puncta of PAD2 to localize in the nucleus. Once in the nucleus, GnRHa stimulated PAD2 citrullinates histone H3 tail arginine residues at sites 2, 8, and 17 within 30 minutes; however, this effect and PAD2 nuclear localization was blunted by incubation of the cells with the pan-PAD inhibitor, biphenyl-benzimidazole-Cl-amidine. Given that PAD2 citrullinates histones in gonadotropes, we next analyzed the functional consequence of PAD2 inhibition on gene expression. Our results show that GnRHa stimulates an increase in LHβ and FSHβ mRNA and that this response is significantly reduced in the presence of the PAD inhibitor biphenyl-benzimidazole-Cl-amidine. Overall, our data suggest that GnRHa stimulates PAD2-catalyzed histone citrullination in gonadotropes to epigenetically regulate gonadotropin gene expression.","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":"30 10","pages":"1081-1091"},"PeriodicalIF":0.0,"publicationDate":"2016-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1210/me.2016-1085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34424318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 17

miR-200 Regulates Endometrial Development During Early Pregnancy. miR-200调控妊娠早期子宫内膜发育

Molecular endocrinology Pub Date : 2016-09-01 Epub Date: 2016-08-17 DOI: 10.1210/me.2016-1050

Patricia T Jimenez, Monica A Mainigi, R Ann Word, W Lee Kraus, Carole R Mendelson

引用次数: 33

Small Heterodimer Partner (NR0B2) Coordinates Nutrient Signaling and the Circadian Clock in Mice. 异源二聚体小伙伴（NR0B2）协调小鼠的营养信号转导和昼夜节律。

Molecular endocrinology Pub Date : 2016-09-01 Epub Date: 2016-07-18 DOI: 10.1210/me.2015-1295

Nan Wu, Kang Ho Kim, Ying Zhou, Jae Man Lee, Nicole M Kettner, Jennifer L Mamrosh, Sungwoo Choi, Loning Fu, David D Moore

引用次数: 11

The F0F1 ATP Synthase Complex Localizes to Membrane Rafts in Gonadotrope Cells. F0F1 ATP合成酶复合物定位在性腺细胞膜筏上

Molecular endocrinology Pub Date : 2016-09-01 Epub Date: 2016-08-02 DOI: 10.1210/me.2015-1324

Krystal Allen-Worthington, Jianjun Xie, Jessica L Brown, Alexa M Edmunson, Abigail Dowling, Amy M Navratil, Kurt Scavelli, Hojean Yoon, Do-Geun Kim, Margaret S Bynoe, Iain Clarke, Mark S Roberson

{"title":"The F0F1 ATP Synthase Complex Localizes to Membrane Rafts in Gonadotrope Cells.","authors":"Krystal Allen-Worthington, Jianjun Xie, Jessica L Brown, Alexa M Edmunson, Abigail Dowling, Amy M Navratil, Kurt Scavelli, Hojean Yoon, Do-Geun Kim, Margaret S Bynoe, Iain Clarke, Mark S Roberson","doi":"10.1210/me.2015-1324","DOIUrl":"10.1210/me.2015-1324","url":null,"abstract":"Fertility in mammals requires appropriate communication within the hypothalamic-pituitary-gonadal axis and the GnRH receptor (GnRHR) is a central conduit for this communication. The GnRHR resides in discrete membrane rafts and raft occupancy is required for signaling by GnRH. The present studies use immunoprecipitation and mass spectrometry to define peptides present within the raft associated with the GnRHR and flotillin-1, a key raft marker. These studies revealed peptides from the F0F1 ATP synthase complex. The catalytic subunits of the F1 domain were validated by immunoprecipitation, flow cytometry, and cell surface biotinylation studies demonstrating that this complex was present at the plasma membrane associated with the GnRHR. The F1 catalytic domain faces the extracellular space and catalyzes ATP synthesis when presented with ADP in normal mouse pituitary explants and a gonadotrope cell line. Steady-state extracellular ATP accumulation was blunted by coadministration of inhibitory factor 1, limiting inorganic phosphate in the media, and by chronic stimulation of the GnRHR. Steady-state extracellular ATP accumulation was enhanced by pharmacological inhibition of ecto-nucleoside triphosphate diphosphohydrolases. Kisspeptin administration induced coincident GnRH and ATP release from the median eminence into the hypophyseal-portal vasculature in ovariectomized sheep. Elevated levels of extracellular ATP augmented GnRH-induced secretion of LH from pituitary cells in primary culture, which was blocked in media containing low inorganic phosphate supporting the importance of extracellular ATP levels to gonadotrope cell function. These studies indicate that gonadotropes have intrinsic ability to metabolize ATP in the extracellular space and extracellular ATP may serve as a modulator of GnRH-induced LH secretion. ","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":" ","pages":"996-1011"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34725335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Editorial: Centennial Celebration - An Interview With Dr Myles Brown on Women's Health. 社论:百年庆典——对迈尔斯·布朗医生关于妇女健康的采访。

Molecular endocrinology Pub Date : 2016-09-01 DOI: 10.1210/me.2016-1125

引用次数: 0

Minireview: Insights Into the Structural and Molecular Consequences of the TSH-β Mutation C105Vfs114X. 微型综述:对TSH-β突变C105Vfs114X的结构和分子后果的见解。

Molecular endocrinology Pub Date : 2016-09-01 Epub Date: 2016-07-07 DOI: 10.1210/me.2016-1065

Gunnar Kleinau, Laura Kalveram, Josef Köhrle, Mariusz Szkudlinski, Lutz Schomburg, Heike Biebermann, Annette Grüters-Kieslich

{"title":"Minireview: Insights Into the Structural and Molecular Consequences of the TSH-β Mutation C105Vfs114X.","authors":"Gunnar Kleinau, Laura Kalveram, Josef Köhrle, Mariusz Szkudlinski, Lutz Schomburg, Heike Biebermann, Annette Grüters-Kieslich","doi":"10.1210/me.2016-1065","DOIUrl":"https://doi.org/10.1210/me.2016-1065","url":null,"abstract":"Naturally occurring thyrotropin (TSH) mutations are rare, which is also the case for the homologous heterodimeric glycoprotein hormones (GPHs) follitropin (FSH), lutropin (LH), and choriogonadotropin (CG). Patients with TSH-inactivating mutations present with central congenital hypothyroidism. Here, we summarize insights into the most frequent loss-of-function β-subunit of TSH mutation C105Vfs114X, which is associated with isolated TSH deficiency. This review will address the following question. What is currently known on the molecular background of this TSH variant on a protein level? It has not yet been clarified how C105Vfs114X causes early symptoms in affected patients, which are comparably severe to those observed in newborns lacking any functional thyroid tissue (athyreosis). To better understand the mechanisms of this mutant, we have summarized published reports and complemented this information with a structural perspective on GPHs. By including the ancestral TSH receptor agonist thyrostimulin and pathogenic mutations reported for FSH, LH, and choriogonadotropin in the analysis, insightful structure function and evolutionary restrictions become apparent. However, comparisons of immunogenicity and bioactivity of different GPH variants is hindered by a lack of consensus for functional analysis and the diversity of used GPH assays. Accordingly, relevant gaps of knowledge concerning details of GPH mutation-related effects are identified and highlighted in this review. These issues are of general importance as several previous and recent studies point towards the high impact of GPH variants in differential signaling regulation at GPH receptors (GPHRs), both endogenously and under diseased conditions. Further improvement in this area is of decisive importance for the development of novel targeted therapies. ","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":" ","pages":"954-64"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1210/me.2016-1065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34645279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 9

Minireview: The Link Between ERα Corepressors and Histone Deacetylases in Tamoxifen Resistance in Breast Cancer. 小型综述:ERα辅抑制因子和组蛋白去乙酰化酶在乳腺癌他莫昔芬耐药中的关系。

Molecular endocrinology Pub Date : 2016-09-01 Epub Date: 2016-07-20 DOI: 10.1210/me.2016-1072

Stéphanie Légaré, Mark Basik

{"title":"Minireview: The Link Between ERα Corepressors and Histone Deacetylases in Tamoxifen Resistance in Breast Cancer.","authors":"Stéphanie Légaré, Mark Basik","doi":"10.1210/me.2016-1072","DOIUrl":"https://doi.org/10.1210/me.2016-1072","url":null,"abstract":"Approximately 70% of breast cancers express the estrogen receptor (ER)α and are treated with the ERα antagonist, tamoxifen. However, resistance to tamoxifen frequently develops in advanced breast cancer, in part due to a down-regulation of ERα corepressors. Nuclear receptor corepressors function by attenuating hormone responses and have been shown to potentiate tamoxifen action in various biological systems. Recent genomic data on breast cancers has revealed that genetic and/or genomic events target ERα corepressors in the majority of breast tumors, suggesting that the loss of nuclear receptor corepressor activity may represent an important mechanism that contributes to intrinsic and acquired tamoxifen resistance. Here, the biological functions of ERα corepressors are critically reviewed to elucidate their role in modifying endocrine sensitivity in breast cancer. We highlight a mechanism of gene repression common to corepressors previously shown to enhance the antitumorigenic effects of tamoxifen, which involves the recruitment of histone deacetylases (HDACs) to DNA. As an indicator of epigenetic disequilibrium, the loss of ERα corepressors may predispose cancer cells to the cytotoxic effects of HDAC inhibitors, a class of drug that has been shown to effectively reverse tamoxifen resistance in numerous studies. HDAC inhibition thus appears as a promising therapeutic approach that deserves to be further explored as an avenue to restore drug sensitivity in corepressor-deficient and tamoxifen-resistant breast cancers. ","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":" ","pages":"965-76"},"PeriodicalIF":0.0,"publicationDate":"2016-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1210/me.2016-1072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34407273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 43

Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk. 表观基因组的MLL1重编程将早期环境暴露与前列腺癌风险联系起来

Molecular endocrinology Pub Date : 2016-08-01 Epub Date: 2016-05-24 DOI: 10.1210/me.2015-1310

Quan Wang, Lindsey S Trevino, Rebecca Lee Yean Wong, Mario Medvedovic, Jing Chen, Shuk-Mei Ho, Jianjun Shen, Charles E Foulds, Cristian Coarfa, Bert W O'Malley, Ali Shilatifard, Cheryl L Walker

{"title":"Reprogramming of the Epigenome by MLL1 Links Early-Life Environmental Exposures to Prostate Cancer Risk.","authors":"Quan Wang, Lindsey S Trevino, Rebecca Lee Yean Wong, Mario Medvedovic, Jing Chen, Shuk-Mei Ho, Jianjun Shen, Charles E Foulds, Cristian Coarfa, Bert W O'Malley, Ali Shilatifard, Cheryl L Walker","doi":"10.1210/me.2015-1310","DOIUrl":"https://doi.org/10.1210/me.2015-1310","url":null,"abstract":"Tissue and organ development is a time of exquisite sensitivity to environmental exposures, which can reprogram developing tissues to increase susceptibility to adult diseases, including cancer. In the developing prostate, even brief exposure to endocrine-disrupting chemicals (EDCs) can increase risk for developing cancer in adulthood, with disruption of the epigenome thought to play a key role in this developmental reprogramming. We find that EDC-induced nongenomic phosphoinositide 3-kinase; (PI3K) signaling engages the histone methyltransferase mixed-lineage leukemia 1 (MLL1), responsible for the histone H3 lysine 4 trimethylation (H3K4me3) active epigenetic mark, to increase cleavage and formation of active MLL1 dimers. In the developing prostate, EDC-induced MLL1 activation increased H3K4me3 at genes associated with prostate cancer, with increased H3K4me3 and elevated basal and hormone-induced expression of reprogrammed genes persisting into adulthood. These data identify a mechanism for MLL1 activation that is vulnerable to disruption by environmental exposures, and link MLL1 activation by EDCs to developmental reprogramming of genes involved in prostate cancer. ","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":"30 8","pages":"856-71"},"PeriodicalIF":0.0,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1210/me.2015-1310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34578878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 62

Research Resource: A Reference Transcriptome for Constitutive Androstane Receptor and Pregnane X Receptor Xenobiotic Signaling. 研究资源:组成型雄烷受体和孕烷X受体异种信号的参考转录组。

Molecular endocrinology Pub Date : 2016-08-01 Epub Date: 2016-07-13 DOI: 10.1210/me.2016-1095

Scott A Ochsner, Anna Tsimelzon, Jianrong Dong, Cristian Coarfa, Neil J McKenna

{"title":"Research Resource: A Reference Transcriptome for Constitutive Androstane Receptor and Pregnane X Receptor Xenobiotic Signaling.","authors":"Scott A Ochsner, Anna Tsimelzon, Jianrong Dong, Cristian Coarfa, Neil J McKenna","doi":"10.1210/me.2016-1095","DOIUrl":"https://doi.org/10.1210/me.2016-1095","url":null,"abstract":"The pregnane X receptor (PXR) (PXR/NR1I3) and constitutive androstane receptor (CAR) (CAR/NR1I2) members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors are well-characterized mediators of xenobiotic and endocrine-disrupting chemical signaling. The Nuclear Receptor Signaling Atlas maintains a growing library of transcriptomic datasets involving perturbations of NR signaling pathways, many of which involve perturbations relevant to PXR and CAR xenobiotic signaling. Here, we generated a reference transcriptome based on the frequency of differential expression of genes across 159 experiments compiled from 22 datasets involving perturbations of CAR and PXR signaling pathways. In addition to the anticipated overrepresentation in the reference transcriptome of genes encoding components of the xenobiotic stress response, the ranking of genes involved in carbohydrate metabolism and gonadotropin action sheds mechanistic light on the suspected role of xenobiotics in metabolic syndrome and reproductive disorders. Gene Set Enrichment Analysis showed that although acetaminophen, chlorpromazine, and phenobarbital impacted many similar gene sets, differences in direction of regulation were evident in a variety of processes. Strikingly, gene sets representing genes linked to Parkinson's, Huntington's, and Alzheimer's diseases were enriched in all 3 transcriptomes. The reference xenobiotic transcriptome will be supplemented with additional future datasets to provide the community with a continually updated reference transcriptomic dataset for CAR- and PXR-mediated xenobiotic signaling. Our study demonstrates how aggregating and annotating transcriptomic datasets, and making them available for routine data mining, facilitates research into the mechanisms by which xenobiotics and endocrine-disrupting chemicals subvert conventional NR signaling modalities. ","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":"30 8","pages":"937-48"},"PeriodicalIF":0.0,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1210/me.2016-1095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34664762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Phoenixin Activates Immortalized GnRH and Kisspeptin Neurons Through the Novel Receptor GPR173. 凤凰素通过新的受体GPR173激活永生化GnRH和Kisspeptin神经元。

Molecular endocrinology Pub Date : 2016-08-01 Epub Date: 2016-06-06 DOI: 10.1210/me.2016-1039

Alice K Treen, Vicky Luo, Denise D Belsham

{"title":"Phoenixin Activates Immortalized GnRH and Kisspeptin Neurons Through the Novel Receptor GPR173.","authors":"Alice K Treen, Vicky Luo, Denise D Belsham","doi":"10.1210/me.2016-1039","DOIUrl":"https://doi.org/10.1210/me.2016-1039","url":null,"abstract":"Reproductive function is coordinated by kisspeptin (Kiss) and GnRH neurons. Phoenixin-20 amide (PNX) is a recently described peptide found to increase GnRH-stimulated LH secretion in the pituitary. However, the effects of PNX in the hypothalamus, the putative signaling pathways, and PNX receptor have yet to be identified. The mHypoA-GnRH/GFP and mHypoA-Kiss/GFP-3 cell lines represent populations of GnRH and Kiss neurons, respectively. PNX increased GnRH and GnRH receptor (GnRH-R) mRNA expression, as well as GnRH secretion, in the mHypoA-GnRH/GFP cell model. In the mHypoA-Kiss/GFP-3 cell line, PNX increased Kiss1 mRNA expression. CCAAT/enhancer-binding protein (C/EBP)-β, octamer transcription factor-1 (Oct-1), and cAMP response element binding protein (CREB) binding sites are localized to the 5' flanking regions of the GnRH, GnRH-R, and Kiss1 genes. PNX decreased C/EBP-β mRNA expression in both cell models and increased Oct-1 mRNA expression in the mHypoA-GnRH/GFP neurons. PNX increased CREB phosphorylation in both cell models and phospho-ERK1/2 in the mHypoA-GnRH/GFP cell model, whereas inhibiting the cAMP/protein kinase A pathway prevented PNX induction of GnRH and Kiss1 mRNA expression. Importantly, we determined that the G protein-coupled receptor, GPR173, was strongly expressed in both GnRH and kisspeptin cell models and small interfering RNA knockdown of GPR173 prevented the PNX-mediated up-regulation of GnRH, GnRH-R, and Kiss1 mRNA expression and the down-regulation of C/EBP-β mRNA expression. PNX also increased GPR173 mRNA expression in the mHypoA-GnRH/GFP cells. Taken together, these studies are the first to implicate that PNX acts through GPR173 to activate the cAMP/protein kinase A pathway through CREB, and potentially C/EBP-β and/or Oct-1 to increase GnRH, GnRH-R, and Kiss1 gene expression, ultimately having a stimulatory effect on reproductive function. ","PeriodicalId":18812,"journal":{"name":"Molecular endocrinology","volume":"30 8","pages":"872-88"},"PeriodicalIF":0.0,"publicationDate":"2016-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1210/me.2016-1039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34552259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 79