Journal of molecular endocrinology最新文献_第5页

The role of WD40 repeat-containing proteins in endocrine (dys)function. WD40重复序列蛋白在内分泌(日)功能中的作用。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-06-19 Print Date: 2023-07-01 DOI: 10.1530/JME-22-0217

Yalan Hu, Eveline Bruinstroop, Anthony N Hollenberg, Eric Fliers, Anita Boelen

{"title":"The role of WD40 repeat-containing proteins in endocrine (dys)function.","authors":"Yalan Hu, Eveline Bruinstroop, Anthony N Hollenberg, Eric Fliers, Anita Boelen","doi":"10.1530/JME-22-0217","DOIUrl":"10.1530/JME-22-0217","url":null,"abstract":"WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain-containing proteins in nuclear receptor signaling, e.g., as corepressor or coactivator. In the final part of this review, we focus on WD40 domain-containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9741563","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

A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants. 一种独特的黑素皮质素-4受体信号传导谱与肥胖相关的组成活性变异。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-06-12 Print Date: 2023-07-01 DOI: 10.1530/JME-23-0008

Rikus Botha, Shree S Kumar, Natasha L Grimsey, Kathleen G Mountjoy

{"title":"A unique melanocortin-4-receptor signaling profile for obesity-associated constitutively active variants.","authors":"Rikus Botha, Shree S Kumar, Natasha L Grimsey, Kathleen G Mountjoy","doi":"10.1530/JME-23-0008","DOIUrl":"10.1530/JME-23-0008","url":null,"abstract":"The melanocortin-4 receptor (MC4R) plays a critical role in regulating energy homeostasis. Studies on obesogenic human MC4R (hMC4R) variants have not yet revealed how hMC4R maintains body weight. Here, we identified a signaling profile for obesogenic constitutively active H76R and L250Q hMC4R variants transfected in HEK293 cells that included constitutive activity for adenylyl cyclase (AC), cyclic adenosine monophosphate (cAMP) response element (CRE)-driven transcription, and calcium mobilization but not phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) activity. Importantly, the signaling profile included impaired α-melanocyte-stimulating hormone-induced CRE-driven transcription but not impaired α-melanocyte-stimulating hormone-induced AC, calcium, or pERK1/2. This profile was not observed for transfected H158R, a constitutively active hMC4R variant associated with overweight but not obesity. We concluded that there is potential for α-melanocyte-stimulating hormone-induced CRE-driven transcription in HEK293 cells transfected with obesogenic hMC4R variants to be the key predictive tool for determining whether they exhibit loss of function. Furthermore, in vivo, α-melanocyte-stimulating hormone-induced hMC4R CRE-driven transcription may be key for maintaining body weight.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10304906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10082181","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

A time- and space-resolved nuclear receptor atlas in mouse liver. 小鼠肝脏核受体图谱的时空分辨。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-18 Print Date: 2023-07-01 DOI: 10.1530/JME-23-0017

Francesco Paolo Zummo, Alexandre Berthier, Céline Gheeraert, Manjula Vinod, Marie Bobowski-Gérard, Olivier Molendi-Coste, Laurent Pineau, Matthieu Jung, Loic Guille, Julie Chevalier-Dubois, David Dombrowicz, Bart Staels, Jérôme Eeckhoute, Philippe Lefebvre

{"title":"A time- and space-resolved nuclear receptor atlas in mouse liver.","authors":"Francesco Paolo Zummo, Alexandre Berthier, Céline Gheeraert, Manjula Vinod, Marie Bobowski-Gérard, Olivier Molendi-Coste, Laurent Pineau, Matthieu Jung, Loic Guille, Julie Chevalier-Dubois, David Dombrowicz, Bart Staels, Jérôme Eeckhoute, Philippe Lefebvre","doi":"10.1530/JME-23-0017","DOIUrl":"10.1530/JME-23-0017","url":null,"abstract":"The functional versatility of the liver is paramount for organismal homeostasis. Adult liver functions are controlled by a tightly regulated transcription factor network including nuclear receptors (NRs), which orchestrate many aspects of hepatic physiology. NRs are transcription factors sensitive to extracellular cues such as hormones, lipids, xenobiotics, etc. and are modulated by intracellular signaling pathways. While liver functional zonation and adaptability to fluctuating conditions rely on a sophisticated cellular architecture, a comprehensive knowledge of NR functions within liver cell populations is still lacking. As a step toward the accurate mapping of NR functions in the liver, we characterized their levels of expression in the whole liver from C57Bl6/J male mice as a function of time and diet. Nr1d1 (Rev-erba), Nr1d2 (Rev-erbb), Nr1c2 (Pparb/d), and Nr1f3 (Rorg) exhibited a robust cyclical expression in ad libitum-fed mice which was, like most cyclically expressed NRs, reinforced upon time-restricted feeding. In a few instances, cyclical expression was lost or gained as a function of the feeding regimen. NR isoform expression was explored in purified hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal cells. The expression of some NR isoforms, such as Nr1h4 (Fxra) and Nr1b1 (Rara) isoforms, was markedly restricted to a few cell types. Leveraging liver single-cell RNAseq studies yielded a zonation pattern of NRs in hepatocytes, liver sinusoidal cells, and stellate cells, establishing a link between NR subtissular localization and liver functional specialization. In summary, we provide here an up-to-date compendium of NR expression in mouse liver in space and time.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10061198","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

CEBPB/POU2F2 modulates endothelin 1 expression in prehypertensive SHR vascular smooth muscle cells. CEBPB/POU2F2调节高血压前期SHR血管平滑肌细胞内皮素1的表达。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-02 Print Date: 2023-07-01 DOI: 10.1530/JME-22-0178

Tien-Chun Yang, Mei-Hua Lu, Wei-Jie Wang, Jang-Yi Chen

{"title":"CEBPB/POU2F2 modulates endothelin 1 expression in prehypertensive SHR vascular smooth muscle cells.","authors":"Tien-Chun Yang, Mei-Hua Lu, Wei-Jie Wang, Jang-Yi Chen","doi":"10.1530/JME-22-0178","DOIUrl":"10.1530/JME-22-0178","url":null,"abstract":"The pathogenesis of hypertension is not fully understood; endothelin 1 (EDN1) is involved in developing essential hypertension. EDN1 can promote vascular smooth muscle cell (VSMC) proliferation or hypertrophy through autocrine and paracrine effects. Proliferating smooth muscle cells in the aorta are 'dedifferentiated' cells that cause increased arterial stiffness and remodeling. Male SHRs had higher aortic stiffness than normal control male WKY rats. Male SHR VSMCs expressed high levels of the EDN1 gene, but endothelial cells did not. Therefore, it is necessary to understand the molecular mechanism of enhanced EDN1 expression in SHR VSMCs. We identified POU2F2 and CEBPB as the main molecules that enhance EDN1 expression in male SHR VSMCs. A promoter activity analysis confirmed that the enhancer region of the Edn1 promoter in male SHR VSMCs was from -1309 to -1279 bp. POU2F2 and CEBPB exhibited an additive role in the enhancer region of the EdnET1 promoter. POU2F2 or CEBPB overexpression sufficiently increased EDN1 expression, and co-transfection with the CEBPB and POU2F2 expression plasmids had additive effects on the activity of the Edn1 promoter and EDN1 secretion level of male WKY VSMCs. In addition, the knockdown of POU2F2 also revealed that POU2F2 is necessary to enhance EDN1 expression in SHR VSMCs. The enhancer region of the Edn1 promoter is highly conserved in rats, mice, and humans. POU2F2 and CEBPB mRNA levels were significantly increased in remodeled human VMSCs. In conclusion, the novel regulation of POU2F2 and CEBPB in VSMCs will help us understand the pathogenesis of hypertension and support the development of future treatments for hypertension.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"71 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10235928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9687286","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

βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids. βHB抑制葡萄糖诱导的GLP-1分泌在GLUTag和人空肠肠。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-01 DOI: 10.1530/JME-22-0115

Erik Elebring, Anna Casselbrant, Sara M T Persson, Lars Fändriks, Ville Wallenius

{"title":"βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids.","authors":"Erik Elebring, Anna Casselbrant, Sara M T Persson, Lars Fändriks, Ville Wallenius","doi":"10.1530/JME-22-0115","DOIUrl":"https://doi.org/10.1530/JME-22-0115","url":null,"abstract":"Ingestion of nutrients stimulates incretin secretion from enteroendocrine cells (EECs) of the epithelial layer of the gut. Glucagon-like peptide-1 (GLP-1) is one of these incretins that stimulate postprandial insulin release and signal satiety to the brain. Understanding the regulation of incretin secretion might open up new therapeutic options for obesity and type-2 diabetes mellitus. To investigate the inhibitory effect of the ketone body β-hydroxybutyrate (βHB) on glucose-induced GLP-1 secretion from EECs, in vitro cultures of murine GLUTag cells and differentiated human jejunal enteroid monolayers were stimulated with glucose to induce GLP-1 secretion. The effect of βHB on GLP-1 secretion was studied using ELISA and ECLIA methods. GLUTag cells stimulated with glucose and βHB were analysed using global proteomics focusing on cellular signalling pathways and the results were verified by Western blot. Results demonstrated βHB had a significant inhibitory effect on glucose-induced GLP-1 secretion at a dose of 100 mM in GLUTag cells. In differentiated human jejunal enteroid monolayers, glucose-induced secretion of GLP-1 was inhibited at a much lower dose of 10 mM βHB. The addition of βHB to GLUTag cells resulted in decreased phosphorylation of kinase AKT and transcription factor STAT3 and also influenced the expressions of signalling molecule IRS-2, kinase DGKε and receptor FFAR3. In conclusion, βHB displays an inhibitory effect on glucose-induced GLP-1 secretion in vitro in GLUTag cells and in differentiated human jejunal enteroid monolayers. This effect may be mediated through multiple downstream mediators of G-protein coupled receptor activation, such as PI3K signalling.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9684446","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

BMAL1 regulates osteoblast differentiation through mTOR/GSK3β/β-catenin pathway. BMAL1通过mTOR/GSK3β/β-catenin通路调控成骨细胞分化。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-05-01 DOI: 10.1530/JME-22-0181

Huixia Li, Hui Meng, Min Xu, Xin Gao, Xulei Sun, Xinxin Jin, Hongzhi Sun

{"title":"BMAL1 regulates osteoblast differentiation through mTOR/GSK3β/β-catenin pathway.","authors":"Huixia Li, Hui Meng, Min Xu, Xin Gao, Xulei Sun, Xinxin Jin, Hongzhi Sun","doi":"10.1530/JME-22-0181","DOIUrl":"https://doi.org/10.1530/JME-22-0181","url":null,"abstract":"Bone mass declines with age and its maintenance is tightly linked to osteoblasts (crucial bone-building cells). Although disruption of the peripheral circadian clock is involved in various pathologies including aging-related diseases, evidence regarding how the peripheral clock regulates bone mass remains elusive. In the present study, we aimed to elucidate the effects of Bmal1 (the key activator of the peripheral circadian clock system) knockdown by lentivirus-mediated shRNA on osteoblast differentiation and its related mechanisms. We found that the expression of osteogenic markers, alkaline phosphatase activity, and mineralization were decreased, whereas apoptosis and inflammatory response were increased in Bmal1 knockdown osteoblasts. In addition, Bmal1 knockdown promoted ERK and JNK phosphorylation, as well as mTOR activity, whereas mTOR inhibition by rapamycin abrogated Bmal1 knockdown-mediated effects on osteoblast differentiation and mineralization capacity. Remarkably, Bmal1 knockdown in osteoblasts inhibited GSK3β/β-catenin signaling with decreased β-catenin expression and GSK-3β phosphorylation at serine 9, while GSK3β inhibition with TDZD-8, but not WNT3a or SKL2001, rescued Bmal1 knockdown-induced defects in osteoblast differentiation. Moreover, rapamycin partly nullified the suppression of Bmal1 knockdown on β-catenin expression and GSK-3β phosphorylation. Collectively, overall data indicated that circadian gene Bmal1 regulated osteoblast differentiation and inflammatory response in an mTOR/GSK3β/β-catenin-dependent manner, and thereby may contribute to the mineralization process and bone modeling/remodeling.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9687285","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

RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis. 冉冉升起的新星:靶向G蛋白偶联受体调节能量稳态。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-04-19 Print Date: 2023-05-01 DOI: 10.1530/JME-23-0014

Aqfan Jamaluddin, Caroline M Gorvin

{"title":"RISING STARS: Targeting G protein-coupled receptors to regulate energy homeostasis.","authors":"Aqfan Jamaluddin, Caroline M Gorvin","doi":"10.1530/JME-23-0014","DOIUrl":"10.1530/JME-23-0014","url":null,"abstract":"G protein-coupled receptors (GPCRs) have a critical role in energy homeostasis, contributing to food intake, energy expenditure and glycaemic control. Dysregulation of energy expenditure can lead to metabolic syndrome (abdominal obesity, elevated plasma triglyceride, LDL cholesterol and glucose, and high blood pressure), which is associated with an increased risk of developing obesity, diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular complications. As the prevalence of these chronic diseases continues to rise worldwide, there is an increased need to understand the molecular mechanisms by which energy expenditure is regulated to facilitate the development of effective therapeutic strategies to treat and prevent these conditions. In recent years, drugs targeting GPCRs have been the focus of efforts to improve treatments for type-2 diabetes and obesity, with GLP-1R agonists a particular success. In this review, we focus on nine GPCRs with roles in energy homeostasis that are current and emerging targets to treat obesity and diabetes. We discuss findings from pre-clinical models and clinical trials of drugs targeting these receptors and challenges that must be overcome before these drugs can be routinely used in clinics. We also describe new insights into how these receptors signal, including how accessory proteins, biased signalling, and complex spatial signalling could provide unique opportunities to develop more efficacious therapies with fewer side effects. Finally, we describe how combined therapies, in which multiple GPCRs are targeted, may improve clinical outcomes and reduce off-target effects.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10160555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9687287","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

PPP2R2A promotes testosterone secretion in Hu sheep Leydig cells via activation of the AKT/mTOR signaling pathway. PPP2R2A通过激活AKT/mTOR信号通路促进虎羊间质细胞睾酮分泌。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-04-17 Print Date: 2023-05-01 DOI: 10.1530/JME-22-0130

Xiaodan Li, Xiaolei Yao, Yongjin Bao, Kaiping Deng, Mingtian Deng, Fan Yang, Xuan Sun, Peihua You, Qingxian Cai, Feng Wang

{"title":"PPP2R2A promotes testosterone secretion in Hu sheep Leydig cells via activation of the AKT/mTOR signaling pathway.","authors":"Xiaodan Li, Xiaolei Yao, Yongjin Bao, Kaiping Deng, Mingtian Deng, Fan Yang, Xuan Sun, Peihua You, Qingxian Cai, Feng Wang","doi":"10.1530/JME-22-0130","DOIUrl":"10.1530/JME-22-0130","url":null,"abstract":"The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme complex that plays a vital role in regulating male reproductive activities. However, as an essential member of the PP2A family, the physiological functions of PP2A regulatory subunit B55α (PPP2R2A) in testis remain inconclusive. Hu sheep are noted for their reproductive precocity and fertility, and are ideal models for the study of male reproductive physiology. Here, we analyzed the expression patterns of PPP2R2A in the male Hu sheep reproductive tract at different developmental stages and further investigated its role in testosterone secretion and its underlying mechanisms. In this study, we found that there were temporal and spatial differences in PPP2R2A protein expression in the testis and epididymis, especially the expression abundance in the testis at 8 months old (8M) was higher than that at 3 months old (3M). Interestingly, we observed that PPP2R2A interference reduced the testosterone levels in the cell culture medium, which is accompanied by a reduction in Leydig cell proliferation and an elevation in Leydig cell apoptosis. The level of reactive oxygen species in cells increased significantly, while the mitochondrial membrane potential (ΔΨm) decreased significantly after PPP2R2A deletion. Meanwhile, the mitochondrial mitotic protein DNM1L was significantly upregulated, while the mitochondrial fusion proteins MFN1/2 and OPA1 were significantly downregulated after PPP2R2A interference. Furthermore, PPP2R2A interference suppressed the AKT/mTOR signaling pathway. Taken together, our data indicated that PPP2R2A enhanced testosterone secretion, promoted cell proliferation, and inhibited cell apoptosis in vitro, all of which were associated with the AKT/mTOR signaling pathway.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10043368","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

CTCF variant begets to short stature by down-regulation of IGF1. CTCF变体通过下调IGF1导致身材矮小。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-04-05 Print Date: 2023-05-01 DOI: 10.1530/JME-22-0193

Hong Chen, Weiyu Li, Suping Zhang, Yunteng Sun, Yiping Shen, Ruimin Chen

{"title":"CTCF variant begets to short stature by down-regulation of IGF1.","authors":"Hong Chen, Weiyu Li, Suping Zhang, Yunteng Sun, Yiping Shen, Ruimin Chen","doi":"10.1530/JME-22-0193","DOIUrl":"10.1530/JME-22-0193","url":null,"abstract":"Pathogenic variants in the transcription factor CCCTC-binding factor (CTCF) are associated with mental retardation, autosomal dominant 21 (MRD21, MIM#615502). Current studies supported the strong relationship between CTCF variants and growth, yet the mechanism of CTCF mutation leading to short stature is not known. Clinical information, treatment regimens, and follow-up outcomes of a patient with MRD21 were collected. The possible pathogenic mechanisms of CTCF variants leading to short stature were investigated using immortalized lymphocyte cell lines (LCLs), HEK-293T, and immortalized normal human liver cell lines (LO2). This patient received long-term treatment with recombinant human growth hormone (rhGH) which resulted in an increased height of 1.0 SDS. She had low serum insulin-like growth factor 1 (IGF1) before the treatment and the IGF1 level was not significantly increased during the treatment (-1.38 ± 0.61 SDS). The finding suggested that the CTCF R567W variant could have impaired IGF1 production pathway. We further demonstrated that the mutant CTCF had a reduced ability to bind to the promoter region of IGF1, consequently significantly reducing the transcriptional activation and expression of IGF1. Our novel results demonstrated a direct positive regulation of CTCF on the transcription of the IGF1 promoter. The impaired IGF1 expression due to CTCF mutation may explain the substandard effect of rhGH treatment on MRD21 patients. This study provided novel insights into the molecular basis of CTCF-associated disorder.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 4","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10160550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10043356","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

Cryo-electron microscopy structures of human thyroid peroxidase (TPO) in complex with TPO antibodies. 人甲状腺过氧化物酶(TPO)与TPO抗体复合物的低温电镜结构。

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2023-04-01 DOI: 10.1530/JME-22-0149

Stuart Baker, Ricardo Núñez Miguel, Daniel Thomas, Michael Powell, Jadwiga Furmaniak, Bernard Rees Smith

{"title":"Cryo-electron microscopy structures of human thyroid peroxidase (TPO) in complex with TPO antibodies.","authors":"Stuart Baker, Ricardo Núñez Miguel, Daniel Thomas, Michael Powell, Jadwiga Furmaniak, Bernard Rees Smith","doi":"10.1530/JME-22-0149","DOIUrl":"https://doi.org/10.1530/JME-22-0149","url":null,"abstract":"Determination of the structure of the extracellular domain of human thyroid peroxidase (hTPO) by cryo-electron microscopy (cryo-EM) is described. TPO, purified to homogeneity was complexed with the hTPO monoclonal autoantibody 2G4 Fab and also with a mouse monoclonal TPO antibody 4F5 Fab (which competes with autoantibody binding to TPO). Both complexes were analysed by cryo-EM. The two structures (global resolution 3.92 and 3.4 Å for the 2G4 complex and 4F5 complex, respectively) show TPO as a monomer with four domains; the N-terminal domain, the peroxidase domain (POD), the complement control protein (CCP)-like domain and the epidermal growth factor-like domain which are all visible in the structures. The relative positions of the domains are fixed with a disulphide bond between cysteine residues Cys146 in the POD and Cys756 in the CCP domain preventing significant flexibility of the molecule. The entrance to the enzyme active site, the haem group and the calcium binding site are clearly visible on the opposite side of the TPO molecule from the 2G4 and 4F5 binding sites. Extensive interactions are seen between TPO and the two antibodies which both bind to distinct epitopes on the POD domain, including some residues in the immunodominant region B mainly via different residues. However, the epitopes of the two antibodies contain three shared TPO residues. This is the first high-resolution structure of TPO to be reported and it should help guide the development of new inhibitors of TPO enzyme activity for therapeutic applications.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"70 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9986399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10855512","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