Journal of molecular endocrinology最新文献_第2页

Syndecans modulate ghrelin receptor signaling. Syndecans能调节胃泌素受体的信号转导。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2024-12-19 Print Date: 2025-01-01 DOI: 10.1530/JME-24-0070

Karina Prins, Noa Mutsters, Femke Volker, Martin Huisman, Rosinda Mies, Patric J D Delhanty, Jenny A Visser

{"title":"Syndecans modulate ghrelin receptor signaling.","authors":"Karina Prins, Noa Mutsters, Femke Volker, Martin Huisman, Rosinda Mies, Patric J D Delhanty, Jenny A Visser","doi":"10.1530/JME-24-0070","DOIUrl":"10.1530/JME-24-0070","url":null,"abstract":"Ghrelin is a gut hormone that enhances food intake and growth hormone secretion through its G-protein coupled receptor, the growth hormone secretagogue receptor (GHSR). Recently, we have shown that ghrelin interacts with syndecans (SDCs), a family of membrane proteins known to modulate hypothalamic appetite signaling. Here, we investigated whether SDCs impact ghrelin signaling at GHSR by assessing ghrelin-induced intracellular Ca2+ mobilization (iCa2+) and inositol phosphate 1 (IP1) production in HEK293 cells. Compared with controls, the overexpression of SDCs dose-dependently increased the maximum iCa2+ response two- to four-fold, without affecting EC50. The IP1 response was similarly amplified by SDCs, but it also indicated that they reduce constitutive (ghrelin-independent) activity of GHSR. These enhanced responses occurred despite a SDC dose-dependent reduction in plasma membrane GHSR levels. Although ghrelin-stimulated Gαq activation was unaltered by SDC1 expression, it failed to restore iCa2+ responsiveness in GNAQ/11 knockout cells, indicating dependence on Gαq/11, not another Gα subunit. This suggests that SDCs modulate either signaling downstream of Gαq/11 or quenching of β-arrestin2 recruitment to GHSR. Indeed, expression of SDCs at levels that only modestly suppress cell surface receptor reduced ghrelin-induced β-arrestin2 recruitment by ∼80%. SDC co-expression also delayed the peak β-arrestin2 response. However, peak β-arrestin2 recruitment follows the peak iCa2+ response, making it unclear whether reduced β-arrestin2 recruitment potentiated Ca2+ signaling. Altogether, SDCs enhanced iCa2+/IP1 and reduced β-arrestin2 recruitment by GHSR in response to ghrelin, likely by modulating signaling downstream of Gαq. This could be a novel mechanism through which SDCs affect metabolism and obesity.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676058","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

Continuing the success of Journal of Endocrinology and Journal of Molecular Endocrinology: Editor-in-Chief handover. 延续《内分泌学杂志》和《分子内分泌学杂志》的成功：主编交接。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2024-12-18 Print Date: 2025-01-01 DOI: 10.1530/JME-24-0124

Martin Haluzik, Gabriela da Silva Xavier

引用次数: 0

Establishment of Star-edited Y1 cells as a novel in vitro functional assay for STAR. 建立星编辑 Y1 细胞，作为 STAR 的新型体外功能测试。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2024-10-29 Print Date: 2024-11-01 DOI: 10.1530/JME-24-0009

Takeshi Sato, Satoshi Narumi, Tetsushi Sakuma, Kazuhiro Shimura, Yosuke Ichihashi, Takashi Yamamoto, Tomohiro Ishii, Tomonobu Hasegawa

{"title":"Establishment of Star-edited Y1 cells as a novel in vitro functional assay for STAR.","authors":"Takeshi Sato, Satoshi Narumi, Tetsushi Sakuma, Kazuhiro Shimura, Yosuke Ichihashi, Takashi Yamamoto, Tomohiro Ishii, Tomonobu Hasegawa","doi":"10.1530/JME-24-0009","DOIUrl":"10.1530/JME-24-0009","url":null,"abstract":"Genetic variants involving steroidogenic acute regulatory protein cause lipoid congenital adrenal hyperplasia, which is characterized by impaired steroidogenesis in the adrenal glands and gonads. Functional assessment of variant STAR proteins is necessary for an accurate genetic diagnosis. Ideally, steroidogenic cells should be used to assess the functionality of STAR proteins, but the presence of endogenous STARs in steroidogenic cells precludes such a method. Here, we generated Star-edited cells from steroidogenic Y1 mouse adrenocortical tumor cells by genome editing. Star-edited Y1 cells exhibited very low but measurable cAMP-dependent pregnenolone production. Furthermore, stimulation of the cAMP pathway for 2 weeks resulted in the formation of lipid droplets in the cytoplasm of Star-edited Y1 cells, which resembled the histology of the adrenal glands of patients with lipoid congenital adrenal hyperplasia. The steroidogenic defect of Star-edited Y1 cells can be restored by transient overexpression of mouse Star. We found that human STAR can also restore defective steroidogenesis in Star-edited Y1 cells, and we were able to construct a novel in vitro system to evaluate human STAR variants. Collectively, we established Star-edited Y1 cells that retain the steroidogenic pathway downstream of the Star protein. Star-edited Y1 cells recapitulate the functional and morphological changes of lipoid congenital adrenal hyperplasia and can be used to evaluate the functionality of human STAR variants.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348518","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

CREB activates the MafA promoter through proximal E-boxes and a CCAAT motif in pancreatic β-cells. 在胰腺β细胞中，CREB 通过近端 E-boxes 和 CCAAT motif 激活 MafA 启动子。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2024-10-04 Print Date: 2024-10-01 DOI: 10.1530/JME-24-0023

Yuki Aida, Kohsuke Kataoka

{"title":"CREB activates the MafA promoter through proximal E-boxes and a CCAAT motif in pancreatic β-cells.","authors":"Yuki Aida, Kohsuke Kataoka","doi":"10.1530/JME-24-0023","DOIUrl":"10.1530/JME-24-0023","url":null,"abstract":"MafA is a key transcriptional regulator of pancreatic islet β-cell function. Its target genes include those encoding preproinsulin and the glucose transporter Glut2 (Slc2a2); thus, MafA function is essential for glucose-stimulated insulin secretion. Expression levels of MafA are reduced in β-cells of diabetic mouse models and human subjects, suggesting that β-cell dysfunction associated with type 2 diabetes is attributable to the loss of MafA. On the other hand, MafA is transcriptionally upregulated by incretin hormones through activation of CREB and its co-activator CRTC2. β-cell-specific expression of MafA relies on a distal enhancer element. However, the precise mechanism by which CREB-CRTC2 regulates the enhancer and proximal promoter regions of MafA remains unclear. In this report, we analyzed previously published ChIP-seq data and found that CREB and NeuroD1, a β-cell-enriched transactivator, bound to both the promoter and enhancer regions of human MAFA. A series of reporter assays revealed that CREB activated the enhancer through a conserved cAMP-responsive element (CRE) but stimulated MAFA promoter activity even when the putative CRE was deleted. Two E-box elements and a CCAAT motif, which bind NeuroD1 and ubiquitous NF-Y transcription factors, respectively, were necessary for transcriptional activation of the MAFA promoter by CREB. Genome-wide analysis of CREB-bound loci in β-cells revealed that they were enriched with CCAAT motifs. Furthermore, promoter analysis of the Isl1 gene encoding a β-cell-enriched transcription factor revealed that a CRE-like element and two CCAAT motifs, but not the E-box, were necessary for activation by CREB. These results provide clues to elucidate the detailed mechanism by which CREB regulates MafA as well as β-cell-specific genes.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073105","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

Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells. 多种启动子和增强子差异很可能导致 G6PC2 在人与小鼠胰岛α细胞中的表达增强。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2024-09-18 Print Date: 2024-10-01 DOI: 10.1530/JME-24-0051

Cyrus C Martin, James K Oeser, Tenzin Wangmo, Brian P Flemming, Alan D Attie, Mark P Keller, Richard M O'Brien

{"title":"Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells.","authors":"Cyrus C Martin, James K Oeser, Tenzin Wangmo, Brian P Flemming, Alan D Attie, Mark P Keller, Richard M O'Brien","doi":"10.1530/JME-24-0051","DOIUrl":"10.1530/JME-24-0051","url":null,"abstract":"G6PC2 encodes a glucose-6-phosphatase catalytic subunit that opposes the action of glucokinase in pancreatic islets, thereby modulating the sensitivity of insulin and glucagon secretion to glucose. In mice, G6pc2 is expressed at ~20-fold higher levels in β-cells than in α-cells, whereas in humans G6PC2 is expressed at only ~5-fold higher levels in β-cells. We therefore hypothesize that G6PC2 likely influences glucagon secretion to a greater degree in humans. With a view to generating a humanized mouse that recapitulates augmented G6PC2 expression levels in α-cells, we sought to identify the genomic regions that confer differential mouse G6pc2 expression in α-cells versus β-cells as well as the evolutionary changes that have altered this ratio in humans. Studies in islet-derived cell lines suggest that the elevated G6pc2 expression in mouse β-cells versus α-cells is mainly due to a difference in the relative activity of the proximal G6pc2 promoter in these cell types. Similarly, the smaller difference in G6PC2 expression between α-cells and β-cells in humans is potentially explained by a change in relative proximal G6PC2 promoter activity. However, we show that both glucocorticoid levels and multiple differences in the relative activity of eight transcriptional enhancers between mice and humans likely contribute to differential G6PC2 expression. Finally, we show that a mouse-specific non-coding RNA, Gm13613, whose expression is controlled by G6pc2 enhancer I, does not regulate G6pc2 expression, indicating that altered expression of Gm13613 in a humanized mouse that contains both the human promoter and enhancers should not affect G6PC2 function.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141909929","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

Icariside II protects from marrow adipose tissue (MAT) expansion in estrogen-deficient mice by targeting S100A16. 淫羊藿苷 II 通过靶向 S100A16 保护雌激素缺乏小鼠的骨髓脂肪组织 (MAT) 免受扩张。

IF 3.6 4区医学

Journal of molecular endocrinology Pub Date : 2024-09-18 Print Date: 2024-10-01 DOI: 10.1530/JME-24-0020

Dong Li, Chenhao Cao, Zhuofan Li, Zhiyong Chang, Ping Cai, Chenxi Zhou, Jun Liu, Kaihua Li, Bin Du

{"title":"Icariside II protects from marrow adipose tissue (MAT) expansion in estrogen-deficient mice by targeting S100A16.","authors":"Dong Li, Chenhao Cao, Zhuofan Li, Zhiyong Chang, Ping Cai, Chenxi Zhou, Jun Liu, Kaihua Li, Bin Du","doi":"10.1530/JME-24-0020","DOIUrl":"10.1530/JME-24-0020","url":null,"abstract":"Icariside II, a flavonoid glycoside, is the main component found invivo after the administration of Herba epimedii and has shown some pharmacological effects, such as prevention of osteoporosis and enhancement of immunity. Increased levels of marrow adipose tissue are associated with osteoporosis. S100 calcium-binding protein A16 (S100A16) promotes the differentiation of bone marrow mesenchymal stem cells (BMSCs) into adipocytes. This study aimed to confirm the anti-lipidogenesis effect of Icariside II in the bone marrow by inhibiting S100A16 expression. We used ovariectomy (OVX) and BMSC models. The results showed that Icariside II reduced bone marrow fat content and inhibited BMSCs adipogenic differentiation and S100A16 expression, which correlated with lipogenesis. Overexpression of S100A16 eliminated the inhibitory effect of Icariside II on lipid formation. β-catenin participated in the regulation adipogenesis mediated by Icariside II/S100A16 in the bone. In conclusion, Icariside II protects against OVX-induced bone marrow adipogenesis by downregulating S100A16, in which β-catenin might also be involved.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889503","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

The role of receptor activity-modifying proteins in obesity and diabetes mellitus 受体活性修饰蛋白在肥胖症和糖尿病中的作用

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2024-09-01 DOI: 10.1530/jme-24-0056

Milena A Malcharek, Abigail Pearce, Cheryl A Brighton, David C Hornigold, Graham Ladds

{"title":"The role of receptor activity-modifying proteins in obesity and diabetes mellitus","authors":"Milena A Malcharek, Abigail Pearce, Cheryl A Brighton, David C Hornigold, Graham Ladds","doi":"10.1530/jme-24-0056","DOIUrl":"https://doi.org/10.1530/jme-24-0056","url":null,"abstract":"Receptor activity-modifying proteins (RAMPs) modulate the expression and activity of numerous G protein-coupled receptors, primarily those within class B1. These receptors have important physiological roles, including in the regulation of food intake, energy metabolism, and glucose homeostasis. Dysregulation of these pathways can lead to obesity and diabetes mellitus, which present an ever-expanding global challenge. Whilst the roles of class B1 receptors and their peptide agonists in obesity and diabetes have been investigated, the contribution of RAMPs is less well understood. This review summarises the results of RAMP knockout studies, highlighting the involvement of these proteins in the incidence of disease. It then moves to discuss how receptor, RAMP, and agonist expression changes in disease states, and the benefits (or detriments) of these agonists to the pathways implicated in disease pathophysiology. Whilst much of the data centres around the calcitonin family of receptors, as their interactions with RAMPs are well established, this review then discusses receptors whose role in obesity and diabetes is well founded, but the significance of whose interactions with RAMPs is more recently emerging. The conclusion of this study of the literature is, however, that the information surrounding RAMPs is conflicting and multifaceted, and more research is required to fully understand their contribution to obesity and diabetes.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"39 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264988","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

Pentraxin3 mediates inflammation and adipogenesis in Graves’ orbitopathy pathogenesis Pentraxin3在巴塞杜氏眼眶病发病机制中介导炎症和脂肪生成

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2024-09-01 DOI: 10.1530/jme-24-0039

Min Seok Kim, Hyun Young Park, Soo Hyun Choi, Eun-Ju Chang, JaeSang Ko, Jin Sook Yoon

{"title":"Pentraxin3 mediates inflammation and adipogenesis in Graves’ orbitopathy pathogenesis","authors":"Min Seok Kim, Hyun Young Park, Soo Hyun Choi, Eun-Ju Chang, JaeSang Ko, Jin Sook Yoon","doi":"10.1530/jme-24-0039","DOIUrl":"https://doi.org/10.1530/jme-24-0039","url":null,"abstract":"Pentraxin 3 (PTX3) is a prototypic humoral soluble pattern-recognition molecule known to function in immunity-related inflammation. Given the lack of information on the precise functions of PTX3 in the pathogenesis of Graves’ orbitopathy (GO), this study investigated the role of PTX3 in the inflammation and adipogenesis mechanism of GO. We first compared the PTX3 expression between orbital tissues from patients with GO and normal controls, using real-time polymerase chain reaction, which estimated significantly higher PTX3 transcript levels in the GO tissues than in the normal tissues. In addition, PTX3 production was markedly increased upon interleukin (IL)-1β and adipogenic stimulation. We then evaluated the effects of silencing PTX3 in primary orbital fibroblast cultures by analyzing the expression levels of pro-inflammatory cytokines, adipogenesis-related proteins, and downstream transcription factors in cells transfected with or without a small interfering RNA against PTX3, using western blot. Silencing PTX3 attenuated the IL-1β-induced secretion of pro-inflammatory cytokines, including IL-6, IL-8, monocyte chemotactic protein-1, intercellular adhesion molecule-1, and cyclooxygenase-2, and suppressed the IL-1β-mediated activation of p38 kinase, nuclear factor-κB, and extracellular signal-regulated kinase. Moreover, PTX3 knockdown suppressed adipogenic differentiation, as assessed using Oil Red O staining, as well as the expression of adipogenesis-associated transcription factors including peroxisome proliferator activator-γ, CCAAT/enhancer-binding proteins α and β, adipocyte protein 2, adiponectin, and leptin. Thus, this study suggests that PTX3 plays a significant role in the pathogenesis of GO and may serve as a novel therapeutic target for the condition.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"30 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264989","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

Constitutive internalisation of EP2 differentially regulates G protein signalling EP2 先天性内化可对 G 蛋白信号进行不同程度的调节

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2024-04-01 DOI: 10.1530/jme-23-0153

Abigail R. Walker, Holly Ann Parkin, Sung Hye Kim, Vasso Terzidou, David F Woodward, Phillip R Bennett, Aylin C. Hanyaloglu

{"title":"Constitutive internalisation of EP2 differentially regulates G protein signalling","authors":"Abigail R. Walker, Holly Ann Parkin, Sung Hye Kim, Vasso Terzidou, David F Woodward, Phillip R Bennett, Aylin C. Hanyaloglu","doi":"10.1530/jme-23-0153","DOIUrl":"https://doi.org/10.1530/jme-23-0153","url":null,"abstract":"The prostanoid G protein-coupled receptor (GPCR) EP2 is widely expressed and implicated in endometriosis, osteoporosis, obesity, pre-term labour, and cancer. Internalisation and intracellular trafficking are critical for shaping GPCR activity, yet little is known regarding spatial programming of EP2 signalling and whether this can be exploited pharmacologically. Using three EP2-selective ligands that favour activation of different EP2 pathways, we show that EP2 undergoes limited agonist-driven internalisation but is constitutively internalised via dynamin-dependent, β-arrestin-independent pathways. EP2 was constitutively trafficked to early and very early endosomes (VEE) which was not altered by ligand activation. APPL1, a key adaptor and regulatory protein of the VEE, did not impact EP2 agonist-mediated cAMP. Internalisation was required for ~70% of the acute butaprost- and AH13205-mediated cAMP signalling, yet PGN9856i, a Gαs biased agonist, was less dependent on receptor internalisation for its cAMP signalling, particularly in human term pregnant myometrial cells that endogenously express EP2. Inhibition of EP2 internalisation partially reduced calcium signalling activated by butaprost or AH13205 and had no effect on PGE2 secretion. This indicates an agonist-dependent differential spatial requirement for Gαs and Gαq/11 signalling and a role for plasma membrane initiated Gαq/11-Ca2+-mediated PGE2 secretion. These findings reveal a key role for EP2 constitutive internalisation in its signalling and potential spatial bias in mediating its downstream functions. This in turn could highlight important considerations for future selective targeting of EP2 signalling pathways.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"19 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140629693","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

ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer ZMIZ1 可增强乳腺癌中 ERα 依赖性 E2F2 的表达

IF 3.5 4区医学

Journal of molecular endocrinology Pub Date : 2024-04-01 DOI: 10.1530/jme-23-0133

Weiye Zhao, Susanna F Rose, Ryan Blake, Aňze Godicelj, Amy E Cullen, Jack Stenning, Lucy Beevors, Marcel Gehrung, Sanjeev Kumar, Kamal Kishore, Ashley Sawle, Matthew Eldridge, Federico M Giorgi, Katherine S Bridge, Florian Markowetz, Andrew N Holding

{"title":"ZMIZ1 enhances ERα-dependent expression of E2F2 in breast cancer","authors":"Weiye Zhao, Susanna F Rose, Ryan Blake, Aňze Godicelj, Amy E Cullen, Jack Stenning, Lucy Beevors, Marcel Gehrung, Sanjeev Kumar, Kamal Kishore, Ashley Sawle, Matthew Eldridge, Federico M Giorgi, Katherine S Bridge, Florian Markowetz, Andrew N Holding","doi":"10.1530/jme-23-0133","DOIUrl":"https://doi.org/10.1530/jme-23-0133","url":null,"abstract":"The Estrogen Receptor-alpha (ER) drives 75% of breast cancers. On activation, the ER recruits and assembles a 1-2 MDa transcriptionally active complex. These complexes can modulate tumour growth, and understanding the roles of individual proteins within these complexes can help identify new therapeutic targets. Here, we present the discovery of ER and ZMIZ1 within the same multi-protein assembly by quantitative proteomics, and validated by proximity ligation assay. We characterise ZMIZ1 function by demonstrating a significant decrease in the proliferation of ER-positive cancer cell lines. To establish a role for the ER-ZMIZ1 interaction, we measured the transcriptional changes in the estrogen response post-ZMIZ1 knockdown using an RNA-seq time-course over 24 hours. GSEA analysis of the ZMIZ1-knockdown data identified a specific delay in the response of estradiol-induced cell cycle genes. Integration of ENCODE data with our RNA-seq results identified that ER and ZMIZ1 both bind the promoter of E2F2. We therefore propose that ER and ZMIZ1 interact to enable the efficient estrogenic response at subset of cell cycle genes via a novel ZMIZ1-ER-E2F2 signalling axis. Finally, we show that high ZMIZ1 expression is predictive of worse patient outcome, ER and ZMIZ1 are co-expressed in breast cancer patients in TCGA and METABRIC, and the proteins are co-localised within the nuclei of tumours cell in patient biopsies. In conclusion, we establish that ZMIZ1 is a regulator of the estrogenic cell cycle response and provide evidence of the biological importance of the ER-ZMIZ1 interaction in ER-positive patient tumours, supporting potential clinical relevance.","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"238 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140571954","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