Journal of molecular endocrinology最新文献_第6页

Identification of prolactin receptor variants with diverse effects on receptor signalling. 对受体信号传导具有不同影响的催乳素受体变体的鉴定。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-25 Print Date: 2023-04-01 DOI: 10.1530/JME-22-0164

Caroline M Gorvin, Paul J Newey, Rajesh V Thakker

{"title":"Identification of prolactin receptor variants with diverse effects on receptor signalling.","authors":"Caroline M Gorvin, Paul J Newey, Rajesh V Thakker","doi":"10.1530/JME-22-0164","DOIUrl":"10.1530/JME-22-0164","url":null,"abstract":"The prolactin receptor (PRLR) signals predominantly through the JAK2-STAT5 pathway regulating multiple physiological functions relating to fertility, lactation, and metabolism. However, the molecular pathology and role of PRLR mutations and signalling are incompletely defined, with progress hampered by a lack of reported disease-associated PRLR variants. To date, two common germline PRLR variants are reported to demonstrate constitutive activity, with one, Ile146Leu, overrepresented in benign breast disease, while a rare activating variant, Asn492Ile, is reported to be associated with an increased incidence of prolactinoma. In contrast, an inactivating germline heterozygous PRLR variant (His188Arg) was reported in a kindred with hyperprolactinaemia, while an inactivating compound heterozygous PRLR variant (Pro269Leu/Arg171Stop) was identified in an individual with hyperprolactinaemia and agalactia. We hypothesised that additional rare germline PRLR variants, identified from large-scale sequencing projects (ExAC and GnomAD), may be associated with altered in vitro PRLR signalling activity. We therefore evaluated >300 previously uncharacterised non-synonymous, germline PRLR variants and selected 10 variants for in vitro analysis based on protein prediction algorithms, proximity to known functional domains and structural modelling. Five variants, including extracellular and intracellular domain variants, were associated with altered responses when compared to the wild-type receptor. These altered responses included loss- and gain-of-function activities related to STAT5 signalling, Akt and FOXO1 activity, as well as cell viability and apoptosis. These studies provide further insight into PRLR structure-function and indicate that rare germline PRLR variants may have diverse modulating effects on PRLR signalling, although the pathophysiologic relevance of such alterations remains to be defined.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7614258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10854278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Genetic bases of pheochromocytoma and paraganglioma. 嗜铬细胞瘤和副神经节瘤的遗传基础。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-24 Print Date: 2023-04-01 DOI: 10.1530/JME-22-0167

Alberto Cascón, Bruna Calsina, Maria Monteagudo, Sara Mellid, Alberto Diaz-Talavera, Maria Curras-Freixes, Mercedes Robledo

{"title":"Genetic bases of pheochromocytoma and paraganglioma.","authors":"Alberto Cascón, Bruna Calsina, Maria Monteagudo, Sara Mellid, Alberto Diaz-Talavera, Maria Curras-Freixes, Mercedes Robledo","doi":"10.1530/JME-22-0167","DOIUrl":"10.1530/JME-22-0167","url":null,"abstract":"The genetics of pheochromocytoma and paraganglioma (PPGL) has become increasingly complex over the last two decades. The list of genes involved in the development of these tumors has grown steadily, and there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease. Although genetic diagnosis is achieved in about 75-80% of patients, genetic etiology remains unexplained in a significant percentage of cases. Patients lacking a genetic diagnosis include not only those with apparently sporadic PPGL but also patients with a family history of the disease or with multiple tumors, that meet the criteria to be considered as candidates for carrying germline mutations in yet undiscovered genes. Mutations in known PPGL genes deregulate three main signaling pathways (hypoxia, kinase signaling, and Wnt-signaling pathways), which could be the starting point for the development of personalized treatment for PPGL patients. Furthermore, the integration of results from several genomic high-throughput platforms enables the discovery of regulatory mechanisms that cannot be identified by analyzing each piece of information separately. These strategies are powerful tools for elucidating optimal therapeutic options based on molecular biomarkers in PPGL and represent an important step toward the achievement of precision medicine for patients with metastatic PPGL.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10612070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ERα/ERβ-directed CBS transcription mediates E2β-stimulated hUAEC H2S production. ERα/ERβ导向的CBS转录介导E2β刺激的hUAEC H2S的产生。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-09 Print Date: 2023-02-01 DOI: 10.1530/JME-22-0175

Jin Bai, Thomas J Lechuga, Joshua Makhoul, Hao Yan, Carol Major, Afshan Hameed, Dong-Bao Chen

{"title":"ERα/ERβ-directed CBS transcription mediates E2β-stimulated hUAEC H2S production.","authors":"Jin Bai, Thomas J Lechuga, Joshua Makhoul, Hao Yan, Carol Major, Afshan Hameed, Dong-Bao Chen","doi":"10.1530/JME-22-0175","DOIUrl":"10.1530/JME-22-0175","url":null,"abstract":"Elevated endogenous estrogens stimulate human uterine artery endothelial cell (hUAEC) hydrogen sulfide (H2S) production by selectively upregulating the expression of H2S synthesizing enzyme cystathionine β-synthase (CBS), but the underlying mechanisms are underdetermined. We hypothesized that CBS transcription mediates estrogen-stimulated pregnancy-dependent hUAEC H2S production. Estradiol-17β (E2β) stimulated CBS but not cystathionine γ-lyase (CSE) expression in pregnant human uterine artery ex vivo, which was attenuated by the estrogen receptor (ER) antagonist ICI 182,780. E2β stimulated CBS mRNA/protein and H2S production in primary hUAEC from nonpregnant and pregnant women, but with greater responses in pregnant state; all were blocked by ICI 182,780. Human CBS promoter contains multiple estrogen-responsive elements (EREs), including one ERE preferentially binding ERα (αERE) and three EREs preferentially binding ERβ (βERE), and one full ERE (α/βERE) and one half ERE (½α/βERE) binding both ERα and ERβ. Luciferase assays using reporter genes driven by human CBS promoter with a series of 5'-deletions identified the α/βEREs binding both ERα and ERβ (α/βERE and ½α/βERE) to be important for baseline and E2β-stimulated CBS promoter activation. E2β stimulated ERα/ERβ heterodimerization by recruiting ERα to α/βEREs and βERE, and ERβ to βERE, α/βEREs, and αERE. ERα or ERβ agonist alone trans-activated CBS promoter, stimulated CBS mRNA/protein and H2S production to levels comparable to that of E2β-stimulated, while ERα or ERβ antagonist alone abrogated E2β-stimulated responses. E2β did not change human CSE promoter activity and CSE mRNA/protein in hUAEC. Altogether, estrogen-stimulated pregnancy-dependent hUAEC H2S production occurs by selectively upregulating CBS expression via ERα/ERβ-directed gene transcription.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 2","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9876575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9382261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex hormones and vascular reactivity: a temporal evaluation in resistance arteries of male rats. 性激素和血管反应性:雄性大鼠抵抗动脉的时间评价。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-22-0147

Wender do Nascimento Rouver, Nathalie Tristão Banhos Delgado, Leticia Tinoco Gonçalves, Jéssyca Aparecida Soares Giesen, Charles Santos da Costa, Eduardo Merlo, Eduardo Damasceno Costa, Virginia Soares Lemos, Jones Bernardes Graceli, Roger Lyrio Dos Santos

{"title":"Sex hormones and vascular reactivity: a temporal evaluation in resistance arteries of male rats.","authors":"Wender do Nascimento Rouver, Nathalie Tristão Banhos Delgado, Leticia Tinoco Gonçalves, Jéssyca Aparecida Soares Giesen, Charles Santos da Costa, Eduardo Merlo, Eduardo Damasceno Costa, Virginia Soares Lemos, Jones Bernardes Graceli, Roger Lyrio Dos Santos","doi":"10.1530/JME-22-0147","DOIUrl":"https://doi.org/10.1530/JME-22-0147","url":null,"abstract":"The role of androgens in vascular reactivity is controversial, particularly regarding their age-related actions. The objective of this study was to conduct a temporal evaluation of the vascular reactivity of resistance arteries of young male rats, as well as to understand how male sex hormones can influence the vascular function of these animals. Endothelium-mediated relaxation was characterized in third-order mesenteric arteries of 10-, 12-, 16-, and 18w (week-old) male rats. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L-10 µmol/L) were constructed in arteries previously contracted with phenylephrine (PE, 3 µmol/L), before and after the use of nitric oxide synthase or cyclooxygenase inhibitors. PE concentration-response curves (1 nmol/L-100 μmol/L) were also built. The levels of vascular nitric oxide, superoxide anion, and hydrogen peroxide were assessed and histomorphometry analysis was performed. The 18w group had impaired endothelium-dependent relaxation. All groups showed prostanoid-independent and nitric oxide-dependent vasodilatory response, although this dependence seems to be smaller in the 18w group. The 18w group had the lowest nitric oxide and hydrogen peroxide production, in addition to the highest superoxide anion levels. Besides functional impairment, 18w animals showed morphological differences in third-order mesenteric arteries compared with the other groups. Our data show that time-dependent exposure to male sex hormones appears to play an important role in the development of vascular changes that can lead to impaired vascular reactivity in mesenteric arteries, which could be related to the onset of age-related cardiovascular changes in males.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10540266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

mPRα and PR co-operate in progesterone inhibition of endothelial cell focal adhesion. mPRα和PR在黄体酮抑制内皮细胞局灶黏附中的协同作用。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-22-0073

Yefei Pang, Peter Thomas

{"title":"mPRα and PR co-operate in progesterone inhibition of endothelial cell focal adhesion.","authors":"Yefei Pang, Peter Thomas","doi":"10.1530/JME-22-0073","DOIUrl":"https://doi.org/10.1530/JME-22-0073","url":null,"abstract":"Progesterone causes vascular smooth muscle cell relaxation through membrane progesterone receptors (mPRs), which are members of the progestin and adipoQ receptor (PAQR) family, and nuclear PRs (nPRs). However, beneficial vascular effects of progesterone in preventing pre-atherosclerosis and the involvement of mPRs and nPRs remain unclear. The results show short- to long-term treatments with 100 nM progesterone (P4) and specific agonists for mPRs, OD 02-0, and nPRs, R5020, inhibited pre-atherosclerotic events in human umbilical vein endothelial cells (HUVECs), decreasing focal adhesion (FA) by monocytes, FA signaling, HUVEC migration and invasion, and vinculin expression. Progesterone and OD 02-0, but not R5020, inhibited phosphorylation of Src and focal adhesion kinase, critical kinases of FA signaling, within 20 min and migration and invasion of HUVECs and monocyte adhesion after 3 h. These inhibitory P4 and 02-0 effects were attenuated with MAP kinase and Pi3k inhibitors, indicating involvement of these kinases in this mPR-mediated action. However, after 16 h, OD 02-0 was no longer effective in inhibiting FA signaling, while both progesterone and R5020 decreased the activity of the two kinases. Knockdown of receptor expression with siRNA confirmed that mPRα mediates short-term and nPR long-term inhibitory effects of progesterone on FA signaling. Thus, progesterone inhibition of FA signaling and pre-atherosclerosis is coordinated through mPRα and nPRs.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10592137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Regulation of mineralocorticoid receptor activation by circadian protein TIMELESS. 昼夜节律蛋白对矿物皮质激素受体激活的调控。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-21-0279

Colin D Clyne, Kevin P Kusnadi, Alexander Cowcher, James Morgan, Jun Yang, Peter J Fuller, Morag J Young

{"title":"Regulation of mineralocorticoid receptor activation by circadian protein TIMELESS.","authors":"Colin D Clyne, Kevin P Kusnadi, Alexander Cowcher, James Morgan, Jun Yang, Peter J Fuller, Morag J Young","doi":"10.1530/JME-21-0279","DOIUrl":"https://doi.org/10.1530/JME-21-0279","url":null,"abstract":"The mineralocorticoid receptor (MR) is a ligand activated transcription factor that regulates cardiorenal physiology and disease. Ligand-dependent MR transactivation involves a conformational change in the MR and recruitment of coregulatory proteins to form a unique DNA-binding complex at the hormone response element in target gene promoters. Differences in the recruitment of coregulatory proteins can promote tissue-, ligand- or gene-specific transcriptional outputs. The goal of this study was to evaluate the circadian protein TIMELESS as a selective regulator of MR transactivation. TIMELESS has an established role in cell cycle regulation and DNA repair. TIMELESS may not be central to mammalian clock function and does not bind DNA; however, RNA and protein levels oscillate over 24hr. Co-expression of TIMELESS down-regulated MR transactivation of an MR-responsive reporter in HEK293 cells, yet enhanced transactivation mediated by other steroid receptors. TIMELESS markedly inhibited MR transactivation of synthetic and native gene promoters, and expression of MR target genes in H9c2 cardiac myoblasts. Immunofluorescence showed aldosterone induce colocalization of TIMELESS and MR, although a direct interaction was not confirmed by coimmunoprecipitation. Potential regulation of circadian clock targets cryptochrome 1 and 2 by TIMELESS was not detected. However, our data suggest that these effects may involve TIMELESS coactivation of estrogen receptor alpha (ERα). Taken together, these data suggest that TIMELESS may contribute to MR transcriptional outputs via enhancing ERα inhibitory actions on MR transactivation. Given the variable expression of TIMELESS in different cell types, these data offer new opportunities for the development of MR modulators with selective actions.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10592138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Ataxin-2 in the hypothalamus at the crossroads between metabolism and clock genes. 下丘脑中的Ataxin-2在代谢和时钟基因的十字路口。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-21-0272

Sara Carmo-Silva, Marisa Ferreira-Marques, Clévio Nóbrega, Mariana Botelho, Daniela Costa, Célia A Aveleira, Stefan M Pulst, Luís Pereira de Almeida, Claudia Cavadas

{"title":"Ataxin-2 in the hypothalamus at the crossroads between metabolism and clock genes.","authors":"Sara Carmo-Silva, Marisa Ferreira-Marques, Clévio Nóbrega, Mariana Botelho, Daniela Costa, Célia A Aveleira, Stefan M Pulst, Luís Pereira de Almeida, Claudia Cavadas","doi":"10.1530/JME-21-0272","DOIUrl":"https://doi.org/10.1530/JME-21-0272","url":null,"abstract":"ATXN2 gene, encoding for ataxin-2, is located in a trait locus for obesity. Atxn2 knockout (KO) mice are obese and insulin resistant; however, the cause for this phenotype is still unknown. Moreover, several findings suggest ataxin-2 as a metabolic regulator, but the role of this protein in the hypothalamus was never studied before. The aim of this work was to understand if ataxin-2 modulation in the hypothalamus could play a role in metabolic regulation. Ataxin-2 was overexpressed/re-established in the hypothalamus of C57Bl6/Atxn2 KO mice fed either a chow or a high-fat diet (HFD). This delivery was achieved through stereotaxic injection of lentiviral vectors encoding for ataxin-2. We show, for the first time, that HFD decreases ataxin-2 levels in mouse hypothalamus and liver. Specific hypothalamic ataxin-2 overexpression prevents HFD-induced obesity and insulin resistance. Ataxin-2 re-establishment in Atxn2 KO mice improved metabolic dysfunction without changing body weight. Furthermore, we observed altered clock gene expression in Atxn2 KO that might be causative of metabolic dysfunction. Interestingly, ataxin-2 hypothalamic re-establishment rescued these circadian alterations. Thus, ataxin-2 in the hypothalamus is a determinant for weight, insulin sensitivity and clock gene expression. Ataxin-2's potential role in the circadian clock, through the regulation of clock genes, might be a relevant mechanism to regulate metabolism. Overall, this work shows hypothalamic ataxin-2 as a new player in metabolism regulation, which might contribute to the development of new strategies for metabolic disorders.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10538037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy. 小鼠甲状腺组织缺乏l型氨基酸转运蛋白2可诱导自噬。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-22-0060

Vaishnavi Venugopalan, Maren Rehders, Jonas Weber, Lisa Rodermund, Alaa Al-Hashimi, Tonia Bargmann, Janine Golchert, Vivien Reinecke, Georg Homuth, Uwe Völker, Francois Verrey, Janine Kirstein, Heike Heuer, Ulrich Schweizer, Doreen Braun, Eva K Wirth, Klaudia Brix

{"title":"Lack of L-type amino acid transporter 2 in murine thyroid tissue induces autophagy.","authors":"Vaishnavi Venugopalan, Maren Rehders, Jonas Weber, Lisa Rodermund, Alaa Al-Hashimi, Tonia Bargmann, Janine Golchert, Vivien Reinecke, Georg Homuth, Uwe Völker, Francois Verrey, Janine Kirstein, Heike Heuer, Ulrich Schweizer, Doreen Braun, Eva K Wirth, Klaudia Brix","doi":"10.1530/JME-22-0060","DOIUrl":"https://doi.org/10.1530/JME-22-0060","url":null,"abstract":"Proteolytic cleavage of thyroglobulin (Tg) for thyroid hormone (TH) liberation is followed by TH release from thyroid follicles into the circulation, enabled by TH transporters. The existence of a functional link between Tg-processing cathepsin proteases and TH transporters has been shown to be independent of the hypothalamus-pituitary-thyroid axis. Thus, lack of cathepsin K, combined with genetic defects in the TH transporters Mct8 and Mct10, that is the Ctsk-/-/Mct8-/y/Mct10-/- genotype, results in persistent Tg proteolysis due to autophagy induction. Because amino acid transport by L-type amino acid transporter 2 (Lat2) has been described to regulate autophagy, we asked whether Lat2 availability is affected in Ctsk-/-/Mct8-/y/Mct10-/- thyroid glands. Our data revealed that while mRNA amounts and subcellular localization of Lat2 remained unaltered in thyroid tissue of Ctsk-/-/Mct8-/y/Mct10-/- mice in comparison to WT controls, the Lat2 protein amounts were significantly reduced. These data suggest a direct link between Lat2 function and autophagy induction in Ctsk-/-/Mct8-/y/Mct10-/- mice. Indeed, thyroid tissue of Lat2-/- mice showed enhanced endo-lysosomal cathepsin activities, increased autophagosome formation, and enhanced autophagic flux. Collectively, these results suggest a mechanistic link between insufficient Lat2 protein function and autophagy induction in the thyroid gland of male mice.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10592145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Son of sevenless 1 (SOS1), the RasGEF, interacts with ERα and STAT3 during embryo implantation. 七子1 (SOS1)， RasGEF，在胚胎着床过程中与ERα和STAT3相互作用。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-22-0089

Renjini A Padmanabhan, Damodaranpillai P Zyju, Anand G Subramaniam, Jaya Nautiyal, Malini Laloraya

{"title":"Son of sevenless 1 (SOS1), the RasGEF, interacts with ERα and STAT3 during embryo implantation.","authors":"Renjini A Padmanabhan, Damodaranpillai P Zyju, Anand G Subramaniam, Jaya Nautiyal, Malini Laloraya","doi":"10.1530/JME-22-0089","DOIUrl":"https://doi.org/10.1530/JME-22-0089","url":null,"abstract":"Estrogen accounts for several biological processes in the body; embryo implantation and pregnancy being one of the vital events. This manuscript aims to unearth the nuclear role of Son of sevenless1 (SOS1), its interaction with estrogen receptor alpha (ERα), and signal transducer and activator of transcription 3 (STAT3) in the uterine nucleus during embryo implantation. SOS1, a critical cytoplasmic linker between receptor tyrosine kinase and rat sarcoma virus signaling, translocates into the nucleus via its bipartite nuclear localization signal (NLS) during the 'window of implantation' in pregnant mice. SOS1 associates with chromatin, interacts with histones, and shows intrinsic histone acetyltransferase (HAT) activity specifically acetylating lysine 16 (K16) residue of histone H4. SOS1 is a coactivator of STAT3 and a co-repressor of ERα. SOS1 creates a partial mesenchymal-epithelial transition by acting as a transcriptional modulator. Finally, our phylogenetic tree reveals that the two bipartite NLS surface in reptiles and the second acetyl coenzymeA (CoA) (RDNGPG) important for HAT activity emerges in mammals. Thus, SOS1 has evolved into a moonlighting protein, the special class of multi-tasking proteins, by virtue of its newly identified nuclear functions in addition to its previously known cytoplasmic function.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10538035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis. 褪黑素通过靶向肝脏中的多种细胞类型来抑制炎症和纤维化，减轻饮食诱导的脂肪性肝炎。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-01-01 DOI: 10.1530/JME-22-0075

Liang Xu, Haoran Li, Ouyang Zhang, Fengming Zhang, Menghui Song, Mengchen Ma, Youjuan Zhao, Rongxiu Ding, Dandan Li, Zhixiong Dong, Shengnan Jin, Weiping Han, Chunming Ding

{"title":"Melatonin alleviates diet-induced steatohepatitis by targeting multiple cell types in the liver to suppress inflammation and fibrosis.","authors":"Liang Xu, Haoran Li, Ouyang Zhang, Fengming Zhang, Menghui Song, Mengchen Ma, Youjuan Zhao, Rongxiu Ding, Dandan Li, Zhixiong Dong, Shengnan Jin, Weiping Han, Chunming Ding","doi":"10.1530/JME-22-0075","DOIUrl":"https://doi.org/10.1530/JME-22-0075","url":null,"abstract":"The pathogenesis of nonalcoholic steatohepatitis (NASH), a severe stage of nonalcoholic fatty liver disease, is complex and implicates multiple cell interactions. However, therapies for NASH that target multiple cell interactions are still lacking. Melatonin (MEL) alleviates NASH with mechanisms not yet fully understood. Thus, we herein investigate the effects of MEL on key cell types involved in NASH, including hepatocytes, macrophages, and stellate cells. In a mouse NASH model with feeding of a methionine and choline-deficient (MCD) diet, MEL administration suppressed lipid accumulation and peroxidation, improved insulin sensitivity, and attenuated inflammation and fibrogenesis in the liver. Specifically, MEL reduced proinflammatory cytokine expression and inflammatory signal activation and attenuated CD11C+CD206- M1-like macrophage polarization in the liver of NASH mice. The reduction of proinflammatory response by MEL was also observed in the lipopolysaccharide-stimulated Raw264.7 cells. Additionally, MEL increased liver fatty acid β-oxidation, leading to reduced lipid accumulation, and restored the oleate-loaded primary hepatocytes. Finally, MEL attenuated hepatic stellate cell (HSC) activation and fibrogenesis in the liver of MCD-fed mice and in LX-2 human HSCs. In conclusion, MEL acts on multiple cell types in the liver to mitigate NASH-associated phenotypes, supporting MEL or its analog as potential treatment for NASH.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10351634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1