Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"NUAKs facilitate mTOR-mediated NSCLC proliferation and metastasis by modulating glucose metabolism and inhibiting p53 activity","authors":"Jaithanya Yesupogu Moorthy Babu,&nbsp;Ravi Manoharan","doi":"10.1016/j.bbamcr.2025.119922","DOIUrl":"10.1016/j.bbamcr.2025.119922","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) cells frequently exhibit aberrant glucose metabolism, characterized by elevated aerobic glycolysis, pentose phosphate pathway (PPP), and reduced oxidative phosphorylation. However, the specific mechanisms underlying the abnormal activation of glucose metabolism and its contribution to NSCLC tumorigenesis remain incompletely elucidated. In this study, we observed that both NUAK1 and NUAK2 mRNA expression levels were significantly elevated in NSCLC tissues compared to non-tumor tissues, and that high NUAK1/2 expression correlated with poor prognosis in NSCLC patients. Furthermore, NUAK1/2 promotes aerobic glycolysis and PPP in NSCLC cells and stimulates cellular proliferation and migration. Depletion or inhibition of NUAK1/2 results in decreased aerobic glycolysis, PPP activity, cell proliferation, and migration, leading to increased apoptosis of NSCLC cells. Mechanistically, NUAK1/2 enhances mTOR activity by suppressing the activity of p53, thereby promoting NSCLC cell growth and metastasis through the promotion of aerobic glycolysis and PPP. Our findings suggest that NUAK1/2 plays a crucial role in glucose reprogramming and tumorigenesis in NSCLC cells, indicating that targeting NUAK1/2 may represent a potential therapeutic strategy for NSCLC metabolism.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119922"},"PeriodicalIF":4.6,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel therapeutic insights into pathological cardiac hypertrophy: tRF-16-R29P4PE regulates PACE4 and metabolic pathways","authors":"Feng Wang ,&nbsp;Ping Li ,&nbsp;Xinxin Yan ,&nbsp;Anna Yue ,&nbsp;Jingyi Xu ,&nbsp;Yaqing Shao ,&nbsp;Kaiyu Zhang ,&nbsp;Qian Zhang ,&nbsp;Yuan Li ,&nbsp;Kangyun Sun","doi":"10.1016/j.bbamcr.2025.119920","DOIUrl":"10.1016/j.bbamcr.2025.119920","url":null,"abstract":"<div><div>Pathological cardiac hypertrophy (PCH) is a complex condition with an incompletely understood pathogenesis. Emerging evidence suggests that transfer RNA-derived small RNAs (tsRNAs) may play a significant role in various cellular processes, yet their impact on PCH remains unexplored. In this study, we performed tsRNA sequencing on plasma samples from PCH patients and identified a marked decrease in the expression of tRNA-related fragment 16-R29P4PE (tRF-16-R29P4PE), a specific tsRNA fragment, with a diagnostic area under the curve value of 0.7750. Using Angiotensin II (Ang II)-stimulated H9c2 cardiomyocytes as an <em>in vitro</em> model and Sprague-Dawley rats as an <em>in vivo</em> model, we investigated the effects of tRF-16-R29P4PE minic/inhibitors and silencing of the paired basic amino acid cleaving system 4 (PACE4) gene. Our results demonstrated that modulating tRF-16-R29P4PE expression significantly reduced brain natriuretic peptide (BNP) and free fatty acid levels while enhancing ATP production, glucose levels, and mitochondrial membrane potential. These effects were accompanied by the downregulation of PACE4, hypoxia-inducible factor-1α (HIF-1α), glucose transporter-4 (GLUT-4), and medium-chain acyl-CoA dehydrogenase (MCAD), as well as the upregulation of peroxisome proliferator-activated receptor α (PPARα). Animal experiments revealed that tRF-16-R29P4PE minic improved cardiac function, reduced myocardial fibrosis, and mitigated metabolic disorders and mitochondrial damage. Furthermore, co-immunoprecipitation (Co-IP) and molecular docking assays confirmed a direct interaction between PACE4 and HIF-1α, and luciferase reporter assays identified PACE4 as a direct target of tRF-16-R29P4PE. By regulating the PACE4 and HIF-1α/PPARα signaling pathways, tRF-16-R29P4PE alleviates PCH, providing a promising molecular target for therapeutic intervention.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119920"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Connexin 43 dephosphorylation mediates the Dchs1/YAP/TEAD signaling pathway to induce cardiac fibrosis","authors":"Min Wang ,&nbsp;Wanning Li ,&nbsp;Yaqing Shao ,&nbsp;Feng Wang ,&nbsp;Ying Huang ,&nbsp;Chenchen Wei ,&nbsp;Ping Li ,&nbsp;Kangyun Sun ,&nbsp;Xinxin Yan ,&nbsp;Zhongshan Gou","doi":"10.1016/j.bbamcr.2025.119919","DOIUrl":"10.1016/j.bbamcr.2025.119919","url":null,"abstract":"<div><h3>Background</h3><div>The gap junction protein connexin 43 (Cx43) has been implicated in the development of cardiac fibrosis. Our previous findings revealed that Cx43 dephosphorylation at serine 282 (S282) is related to cardiomyocyte apoptosis and arrhythmias in hearts damaged by ischemia/reperfusion. In this study, we investigated the role of Cx43 S282 phosphorylation in cardiac fibrosis.</div></div><div><h3>Methods</h3><div>We used angiotensin II (Ang II) intervention in mice to establish an in vivo cardiac fibrosis model and transforming growth factor β-1 (TGF-β1) intervention in cardiac myofibroblasts to establish an in vitro fibrosis model. The expression of Cx43 S282 phosphorylation was examined in the in vivo and in vitro models. To further confirm the effect of Cx43 S282 phosphorylation on cardiac fibrosis, we transfected cardiac myofibroblasts with lentiviral bodies in vitro, and injected myocardium with adenovirus in vivo to establish the over-expression of phosphorylation of Cx43 S282 locus and mutant groups. We sequenced the mRNA of the in vitro group using gene set enrichment analysis (GSEA) and normalized enrichment scoring (NES) to investigate the signaling pathway by which p282-Cx43 affects myocardial fibrosis (MF). The role of the Hippo signaling pathway in phosphorylation at the Cx43 282 site was further validated.</div></div><div><h3>Results</h3><div>In an in vivo and in vitro model of cardiac fibrosis, the level of phosphorylation of Cx43 S282 was reduced. Mutation of Cx43 S282 to a less phosphorylatable form (S282A) resulted in elevated levels of fibrosis markers, suggesting a critical antifibrotic role for phosphorylated Cx43 S282. Increased phosphorylation of Cx43 S282 produced an inhibitory effect on fibrosis. Enrichment analysis of mRNA sequencing in the mutant model group indicated that the Hippo signaling pathway was involved in the fibrosis process. Cx43 S282 phosphorylation increased the expression of Dchs1 gene, which activates the phosphorylation of yes-associated protein (YAP) and inhibits the YAP/TEAD signaling pathway to inhibit fibrosis development.</div></div><div><h3>Conclusions</h3><div>This study suggests that the phosphorylation of Cx43 S282 could be an effective antifibrotic target in cardiac fibroblasts. This indicates a novel mechanism and a molecular target that may hold promise for treating cardiac fibrosis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119919"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT3 impairment and MnSOD hyperacetylation in trophoblast dysfunction and preeclampsia","authors":"Yangnan Ding,&nbsp;Xuewei Zhang,&nbsp;Jin Li,&nbsp;Yina Li,&nbsp;Linlin Zhang,&nbsp;Enwu Yuan","doi":"10.1016/j.bbamcr.2025.119915","DOIUrl":"10.1016/j.bbamcr.2025.119915","url":null,"abstract":"<div><div>Preeclampsia (PE) is a prevalent obstetric disorder that affects 2–8 % of pregnancies worldwide. Trophoblasts, which are crucial functional cells in the placenta, play a significant role in the development of PE due to inadequate invasion. Sirtuin 3 (SIRT3) is an NAD⁺ − dependent mitochondrial deacetylase, that positively modulates energy metabolism, mitochondrial biogenesis, and protection against oxidative stress. However, the role of SIRT3 in trophoblast dysfunction and the pathogenesis of PE remains unclear. In this study, we aim to investigate the functional role of SIRT3 in PE and explore the underlying mechanism. Our results demonstrated that human PE placentas exhibited reduced expression of SIRT3. <em>In vitro</em> experiments showed that hypoxia promoted SIRT3 expression, while oxidative stress inhibited SIRT3 expression in HTR-8/SVneo cells. The reduced SIRT3 expression inhibited the proliferation and migration of trophoblast cells while also increasing levels of reactive oxygen species and inflammatory factors. As a deacetylase, SIRT3 deficiency increased the acetylation level of manganese superoxide dismutase (MnSOD), a key mitochondrial antioxidant enzyme, subsequently reducing its activity. These effects associated with reduced SIRT3 expression could be reversed by treatment with MnSOD mimetics TEMPO and overexpression of MnSOD. All these results suggested that diminished SIRT3 expression leaded to MnSOD hyperacetylation and inactivation, contributing to trophoblast dysfunction and the pathogenesis of PE.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119915"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143395690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia reduces SLC27A5 to promote hepatocellular carcinoma proliferation by repressing HNF4A","authors":"Junji Tao ,&nbsp;Yuanyuan Liu ,&nbsp;Xin Tang ,&nbsp;Dan Nie ,&nbsp;Kang Wu ,&nbsp;Kai Wang ,&nbsp;Ni Tang","doi":"10.1016/j.bbamcr.2025.119916","DOIUrl":"10.1016/j.bbamcr.2025.119916","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality globally, with hypoxia recognized as a key factor in its progression. Solute carrier family 27 member 5 (SLC27A5/FATP5), a pivotal enzyme in hepatic fatty acid transport and bile acid metabolism, is frequently downregulated in hepatocellular carcinoma, resulting in poor prognosis. However, the link between hypoxia and the suppression of SLC27A5 in HCC remains to be elucidated. Here, we investigated the hypoxia-induced downregulation of SLC27A5 and its impact on HCC proliferation via the repression of hepatocyte nuclear factor 4 alpha (HNF4A). Utilizing in vitro and in vivo hepatocellular carcinoma models, we have demonstrated that hypoxic conditions significantly reduce SLC27A5 transcription, which is mediated by the suppression of HNF4A. This reduction leads to the activation of the AKT pathway and an increase in cyclin-dependent kinase 2 (CDK2) and Cyclin E1 (CCNE1) expression, promoting the transition from the G1 to S phase of the cell cycle and driving HCC proliferation. Furthermore, we show that the pharmacological activation of HNF4A using Benfluorex, in combination with the AKT inhibitor MK2206, significantly inhibits tumor growth in a subcutaneous MHCC-97H xenograft model, suggesting a synergistic therapeutic potential. Together, our study provides novel insights into the hypoxia-mediated regulatory mechanisms in HCC and highlights the HNF4A/SLC27A5/AKT axis as a promising target for combination therapy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119916"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KLF12 inhibits lipopolysaccharide-induced inflammatory responses, oxidative stress, pyroptosis, and endoplasmic reticulum stress in human airway epithelial cells through inhibition of the NF-κB pathway","authors":"Xiujuan Xu,&nbsp;Yiping Yu","doi":"10.1016/j.bbamcr.2025.119917","DOIUrl":"10.1016/j.bbamcr.2025.119917","url":null,"abstract":"<div><div>Asthma is a common and frequent chronic disease in pediatrics with obvious pathological features, particularly inflammation, oxidative stress, pyroptosis, and endoplasmic reticulum (ER) stress. Some Krüppel-like factors (KLFs), such as KLF2, KLF4, KLF5, and KLF10, have been reported to be associated with several respiratory diseases, including asthma. However, the role of KLF12 in asthma pathogenesis is unknown. Based on the GEO analysis, KLF12 mRNA expression was reduced in asthma patients. We further assessed the role of KLF12 in protecting airway epithelial cells (BEAS-2B cells) against stimuli using an in vitro model of asthma. The results showed that lipopolysaccharide (LPS) stimulation caused a decrease in KLF12 expression. LPS-induced increase in the mRNA levels of inflammatory cytokines TNF-α, IL-6, and IL-8 were attenuated by KLF12 overexpression. LPS induced the production ROS and MDA and reduced the activities of enzymatic antioxidants SOD, CAT, and GSH-Px, which were prevented by KLF12 overexpression. KLF12 overexpression also blocked LPS-induced pyroptosis, as shown by decreased levels of IL-1β, IL-18, and LDH, as well as downregulated expression levels of pyroptosis-related proteins including NLRP3, ASC, cleaved caspase-1, and GSDMD-N. LPS-induced expression levels of ER stress markers GRP78, CHOP, p-eIF2α, and ATF-4 were inhibited by KLF12 overexpression. In addition, the protective effects of KLF12 on LPS-stimulated cells were enhanced by PDTC, an inhibitor of NF-κB. KLF12 knockdown showed an opposite effect to KLF12 overexpression. These results indicated that KLF12 suppressed LPS-induced inflammatory response, oxidative stress, pyroptosis, and ER stress, which were mediated by the inactivation of the NF-κB pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119917"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Filamin A suppresses the expression of ribosomal protein genes by controlling the activity of an EGR1-Sp1-GCN5/PCAF pathway in human cells","authors":"Xiaoye Song ,&nbsp;Yaoyu Pang ,&nbsp;Yun Wei ,&nbsp;Deen Yu ,&nbsp;Ye Wang ,&nbsp;Junwei Gao ,&nbsp;Shuting Zhang ,&nbsp;Qiang Wu ,&nbsp;Juan Wang ,&nbsp;Shasha Zhao ,&nbsp;Wensheng Deng","doi":"10.1016/j.bbamcr.2025.119914","DOIUrl":"10.1016/j.bbamcr.2025.119914","url":null,"abstract":"<div><div>Human ribosome biogenesis requires four types of rRNA molecules and almost eighty cytoplasmic ribosomal proteins (CRPs) to be assembled together. . In the previous work, we showed that cytoskeletal filamin A (FLNA) can suppress rRNA expression in human cells. Thus, we hypothesized that FLNA can modulate the expression of CRPs because human cells have to coordinate cellular ribosome biogenesis. Here, we show that the absence of FLNA enhances the expression of most CRP genes assayed in the work, whereas the presence of FLNA dampens the expression of these CRP genes in several transformed cell types. The analysis of RNA-seq data revealed that FLNA silencing activated the expression of almost all CRPs and many mitochondrial RP genes in SaOS2 cells. These results indicate that FLNA acts as a negative regulator in CRP expression in human cells. Mechanistically, FLNA inhibits the expression of GCN5 and PCAF, which consequently impedes the occupancies of GCN5, PCAF, andH3K9ac at CRP gene loci. Both GCN5 and PCAF participates in the regulation of CRP expression either mediated by FLNA or independently. We show that FLNA silencing activates Sp1 expression and the activation of Sp1 stimulates the expression of <em>Gcn5</em> and <em>Pcaf</em> genes. Further analysis revealed that EGR1 can bind the <em>Sp1</em> gene promoter and activate <em>Sp1</em> transcription. Collectively, this study revealed an EGR1-Sp1-GCN5/PCAF pathway by which FLNA modulates the expression of CRP genes. These findings shed light on how human cells coordinate the expression of CRP genes during ribosomal biogenesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119914"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143405609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-synonymous single nucleotide polymorphisms (nsSNPs) within the extracellular domains of the GPM6A gene impair hippocampal neuron development","authors":"Antonella León ,&nbsp;Ignacio Sallaberry ,&nbsp;Rocío Gutiérrez Fuster ,&nbsp;Facundo Brizuela Sotelo ,&nbsp;Gabriela Inés Aparicio ,&nbsp;Laura Cecilia Estrada ,&nbsp;Camila Scorticati","doi":"10.1016/j.bbamcr.2025.119913","DOIUrl":"10.1016/j.bbamcr.2025.119913","url":null,"abstract":"<div><div>Psychiatric disorders are complex pathologies influenced by both environmental and genetic factors, ultimately leading to synaptic plasticity dysfunction. Altered expression levels of neuronal glycoprotein GPM6a or polymorphisms within the <em>GPM6A</em> gene are associated with neuropsychiatric disorders like schizophrenia, depression, and claustrophobia. This protein promotes neurite outgrowth, filopodia formation, dendritic spine, and synapse maintenance in vitro. Although strong evidence suggests that its extracellular domains (ECs) are responsible for its function, the molecular mechanisms linking GPM6a to the onset of such diseases remain unknown. To gain knowledge of these mechanisms, we characterized new non-synonymous polymorphisms (nsSNPs) within the ECs of GPM6a. We identified six nsSNPs (T71P, T76I, M154V, F156Y, R163Q, and T210N) that impair GPM6a-induced plasticity in neuronal cultures without affecting GPM6a expression, folding, and localization to the cell membrane. However, we observed that some of these modified GPM6a's distribution at the cell membrane. Additionally, one of the nsSNPs exhibited alterations in GPM6a oligomerization, highlighting the importance of this amino acid in establishing homophilic <em>cis</em> interactions. Furthermore, we observed that the ability of GPM6a's extracellular domains to interact and induce cell aggregation was significantly decreased in several of the nsSNP variants studied here. Altogether, these results provide new insights into the key residues within GPM6a's extracellular regions that are crucial for its self-association, which is essential for promoting neuronal morphogenesis. Besides, these findings highlight the importance of reverse genetics approaches to gain knowledge on GPM6a's mechanisms of action and the genetic susceptibility of certain <em>GPM6A</em> variants.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119913"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143395688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel function of the Wnt antagonist secreted frizzled-related protein 4 as a transcriptional regulator of Dickkopf-1, another Wnt antagonist, in glioblastoma cell line U87MG","authors":"Ishmat Ara Yasmin ,&nbsp;Arun Dharmarajan ,&nbsp;Sudha Warrier","doi":"10.1016/j.bbamcr.2025.119918","DOIUrl":"10.1016/j.bbamcr.2025.119918","url":null,"abstract":"<div><div>Wnt/β-catenin pathway dysregulation is associated with glioblastoma multiforme (GBM) pathogenesis and Wnt antagonists are downregulated in GBM. Wnt antagonist secreted frizzled-related protein 4 (sFRP4) has a tissue-specific, anti-metastatic and anti-stemness property. Our lab previously reported that gene silencing of sFRP4 in GBM cell line U87MG increases expression of another Wnt antagonist, Dickkopf-1 (Dkk1) and sFRP4 has a DNA binding ability. These findings in accordance with the nuclear localization of sFRP4 led to our present hypothesis that sFRP4 presumably negatively regulates Dkk1 and it probably interacts with the promoter region of Dkk1. Methylation-specific PCR (MSP), chromatin accessibility real-time PCR (ChART-PCR) assay, chromatin immunoprecipitation (ChIP), and quantitative DNA-protein interaction enzyme-linked immunosorbent assay (qDPI-ELISA) were carried out to test our hypothesis. We demonstrated that sFRP4 overexpression does not alter the methylation status of the Dkk1 promoter region. sFRP4 overexpression inhibits DNA-transcription factor interaction and enables chromatin accessibility to DNase I. Pertinently, sFRP4 has strong putative binding sites in the Dkk1 promoter region and its overexpression disrupts its interaction with the Dkk1 promoter. Interestingly, sFRP4 has the strongest affinity towards the ‐282 to +118 bp region. Downregulation of Dkk1 by overexpressed sFRP4 occurs by inhibition of the direct interaction of sFRP4 with the promoter region of Dkk1 as observed with low concentrations of sFRP4. We report for the first time a novel function of the Wnt antagonist sFRP4 acting as a transcription factor for another Wnt antagonist Dkk1, throwing open a new vista in the complex interplay between different antagonists of the Wnt pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 3","pages":"Article 119918"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hornerin expressed on endothelial cells via interacting with thrombomodulin modulates vascular inflammation and angiogenesis","authors":"Takayuki Okamoto ,&nbsp;Mai Hattori ,&nbsp;Yukiko Katsube ,&nbsp;Junichi Ota ,&nbsp;Kunihiro Asanuma ,&nbsp;Haruki Usuda ,&nbsp;Koichiro Wada ,&nbsp;Koji Suzuki ,&nbsp;Tetsuro Nikai","doi":"10.1016/j.bbamcr.2024.119891","DOIUrl":"10.1016/j.bbamcr.2024.119891","url":null,"abstract":"<div><div>Thrombomodulin is predominantly expressed on vascular endothelial cells and modulates endothelial cell functions by interacting with multiple ligands. The specific thrombomodulin receptor or cofactor active on the endothelial cell surface remains elusive. This study aims to identify interacting partners of thrombomodulin on endothelial cells. Here, using a liquid chromatograph-tandem mass spectrometer, hornerin was identified as a candidate protein. We then investigated hornerin protein and mRNA expression in endothelial cells. Hornerin protein was detected in the mouse endothelium of the aorta and lung. Both human- and mouse-cultured endothelial cells expressed hornerin mRNA and protein. Moreover, immunoprecipitation analysis suggested the direct protein interaction between thrombomodulin and hornerin. Lipopolysaccharides administration increased serum hornerin concentrations in mice and reduced hornerin protein levels on the surface of cultured endothelial cells as same as thrombomodulin protein. Thrombomodulin-targeting siRNA decreased not only thrombomodulin protein levels but also hornerin protein levels in cultured endothelial cells. Thrombomodulin- or hornerin-targeting siRNA impaired tube formation and leukocyte adhesion to endothelial cells. Our findings reveal that hornerin is located on vascular endothelial cells in the presence of thrombomodulin and suggest that endothelial thrombomodulin and hornerin may interact, which may play an important role in endothelial cell functions such as vascular inflammation and angiogenesis.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 2","pages":"Article 119891"},"PeriodicalIF":4.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}