Biochimica et biophysica acta. Molecular cell research最新文献_第3页

Filamin A suppresses the expression of ribosomal protein genes by controlling the activity of an EGR1-Sp1-GCN5/PCAF pathway in human cells

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-10 DOI: 10.1016/j.bbamcr.2025.119914

Xiaoye Song , Yaoyu Pang , Yun Wei , Deen Yu , Ye Wang , Junwei Gao , Shuting Zhang , Qiang Wu , Juan Wang , Shasha Zhao , Wensheng Deng

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 Gcn5 and Pcaf genes. Further analysis revealed that EGR1 can bind the Sp1 gene promoter and activate Sp1 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.

{"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 , Yaoyu Pang , Yun Wei , Deen Yu , Ye Wang , Junwei Gao , Shuting Zhang , Qiang Wu , Juan Wang , Shasha Zhao , 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}

引用次数: 0

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

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-10 DOI: 10.1016/j.bbamcr.2025.119917

Xiujuan Xu, Yiping Yu

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.

{"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, 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}

引用次数: 0

Non-synonymous single nucleotide polymorphisms (nsSNPs) within the extracellular domains of the GPM6A gene impair hippocampal neuron development

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-10 DOI: 10.1016/j.bbamcr.2025.119913

Antonella León , Ignacio Sallaberry , Rocío Gutiérrez Fuster , Facundo Brizuela Sotelo , Gabriela Inés Aparicio , Laura Cecilia Estrada , Camila Scorticati

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 GPM6A 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 cis 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 GPM6A variants.

{"title":"Non-synonymous single nucleotide polymorphisms (nsSNPs) within the extracellular domains of the GPM6A gene impair hippocampal neuron development","authors":"Antonella León , Ignacio Sallaberry , Rocío Gutiérrez Fuster , Facundo Brizuela Sotelo , Gabriela Inés Aparicio , Laura Cecilia Estrada , 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}

引用次数: 0

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

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-10 DOI: 10.1016/j.bbamcr.2025.119918

Ishmat Ara Yasmin , Arun Dharmarajan , Sudha Warrier

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.

{"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 , Arun Dharmarajan , 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}

引用次数: 0

Hornerin expressed on endothelial cells via interacting with thrombomodulin modulates vascular inflammation and angiogenesis 内皮细胞上表达的角蛋白通过与血栓调节蛋白相互作用调节血管炎症和血管生成。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119891

Takayuki Okamoto , Mai Hattori , Yukiko Katsube , Junichi Ota , Kunihiro Asanuma , Haruki Usuda , Koichiro Wada , Koji Suzuki , Tetsuro Nikai

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.

血栓调节蛋白主要在血管内皮细胞上表达，并通过与多种配体相互作用调节内皮细胞功能。内皮细胞表面特定的血栓调节素受体或辅助因子活性尚不明确。本研究旨在确定血栓调节素对内皮细胞的相互作用伙伴。在这里，使用液相色谱-串联质谱仪，角蛋白被确定为候选蛋白。然后我们研究了内皮细胞中角蛋白和mRNA的表达。在小鼠主动脉和肺内皮中检测到Hornerin蛋白。人和小鼠内皮细胞均表达角蛋白mRNA和蛋白。此外，免疫沉淀分析表明血栓调节蛋白和角蛋白之间存在直接的蛋白相互作用。脂多糖增加小鼠血清角蛋白浓度，降低培养内皮细胞表面角蛋白水平，与血栓调节蛋白水平相同。以血栓调节蛋白为靶点的siRNA不仅能降低培养内皮细胞的血栓调节蛋白水平，还能降低角蛋白水平。以血栓调节素或角蛋白为靶点的siRNA会破坏小管的形成和白细胞与内皮细胞的粘附。我们的研究结果表明，在血栓调节蛋白存在的情况下，角蛋白位于血管内皮细胞上，表明内皮血栓调节蛋白和角蛋白可能相互作用，在血管炎症和血管生成等内皮细胞功能中发挥重要作用。

{"title":"Hornerin expressed on endothelial cells via interacting with thrombomodulin modulates vascular inflammation and angiogenesis","authors":"Takayuki Okamoto , Mai Hattori , Yukiko Katsube , Junichi Ota , Kunihiro Asanuma , Haruki Usuda , Koichiro Wada , Koji Suzuki , 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}

引用次数: 0

Enhanced radiotherapy susceptibility in NSCLC through palbociclib-mediated PP5 inhibition 通过帕博西利介导的PP5抑制增强NSCLC的放疗敏感性。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119884

Chao-Yuan Huang , Li-Ju Chen , Grace Chen , Cheng-Yi Wang , Shiao-Ya Hong

Radiotherapy remains a cornerstone in the treatment of non-small cell lung cancer (NSCLC), yet radioresistance often limits its efficacy. Identifying molecular targets that enhance radiosensitivity is crucial to offering both curative and palliative benefits for patients with NSCLC. Utilizing bioinformatics analysis, our study revealed significantly higher expression of PP5 in NSCLC tissues compared to normal tissues. Kaplan-Meier survival analysis also showed that high PP5 expression correlates with poorer overall survival, particularly in patients undergoing radiotherapy, suggesting a role for PP5 in radioresistance. We further demonstrated that PP5 is a critical target of palbociclib, distinct from CDK4/6, influencing radiosensitivity in NSCLC. Palbociclib enhanced radiotherapy susceptibility by inducing sustained DNA damage and AMPK activation. The subsequent cellular event is apoptosis rather than autophagy. Furthermore, the enhanced efficacy of combination therapy was counteracted by an AMPK inhibitor and PP5 activator, underscoring the importance of these pathways in mediating the response. Our findings provide compelling evidence that targeting PP5 can significantly enhance the therapeutic outcomes of radiotherapy in NSCLC. This research offers valuable insights into new combination therapy strategies, highlighting the potential of PP5 as a novel therapeutic target to overcome radioresistance.

放疗仍然是治疗非小细胞肺癌（NSCLC）的基石，但放射耐药往往限制了其疗效。确定增强放射敏感性的分子靶点对于为非小细胞肺癌患者提供治疗和姑息效益至关重要。利用生物信息学分析，我们的研究显示PP5在NSCLC组织中的表达明显高于正常组织。Kaplan-Meier生存分析还显示，PP5高表达与较差的总生存相关，特别是在接受放疗的患者中，这表明PP5在放射耐药中起作用。我们进一步证明PP5是palbociclib的关键靶点，不同于CDK4/6，影响NSCLC的放射敏感性。帕博西尼通过诱导持续DNA损伤和AMPK激活来增强放疗敏感性。随后的细胞事件是细胞凋亡而不是自噬。此外，联合治疗的增强疗效被AMPK抑制剂和PP5激活剂抵消，强调了这些途径在介导反应中的重要性。我们的研究结果提供了令人信服的证据，表明靶向PP5可以显著提高NSCLC放疗的治疗效果。这项研究为新的联合治疗策略提供了有价值的见解，突出了PP5作为克服放射耐药的新治疗靶点的潜力。

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引用次数: 0

RANKL regulates differentially breast cancer stem cell properties through its RANK and LGR4 receptors RANKL通过其RANK和LGR4受体调控乳腺癌干细胞的差异特性。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119888

Alejandro Ordaz-Ramos , Jorge Diaz-Blancas , Aketzalli Martínez-Cruz , Rosario Castro-Oropeza , Cecilia Zampedri , Damaris P Romero-Rodríguez , Mauricio Rodriguez-Dorantes , Jorge Melendez-Zajgla , Vilma Maldonado , Karla Vazquez-Santillan

Background

Breast cancer stem cells (BCSC) are a subpopulation responsible for cancer resistance and relapse. The receptor activator of nuclear factor kappa-Β ligand (RANKL) is a cytokine capable of activating RANK and LGR4 receptors. RANKL/RANK signaling maintains the self-renewal of BCSCs, however, the effect of RANKL via LGR4 remains unclear. Evidence from osteoclasts suggests that RANKL/LGR4 axis disrupts RANK signaling, leading to opposing cellular responses. Anti-RANKL inhibitors are potential agents for eradicating CSCs, but their effect on RANKL/LGR4 signal has not been demonstrated.

Objective

This project aimed to elucidate the role of RANKL in regulating stemness depending on the expression of its receptors.

Methods

We use in vitro and in vivo approaches to evaluate the effects of RANKL inhibition in stemness in low or high-LGR4 expressing cells. Furthermore, we analyze the effects of RANKL stimulation on the stemness of LGR4 or RANK overexpressing cells. Additionally, we evaluated the impact of RANKL/LGR4 signaling in the activity of Wnt/β-catenin and NF-κB signaling pathways.

Results

Our findings indicated that elevated RANKL expression is related to a favorable prognosis in patients with high LGR4 levels. Furthermore, RANKL inhibition decreased BCSC properties in LGR4-low cell lines, while it promoted migration in LGR4-high cells. Additionally, the RANKL/RANK axis activated NF-κB signaling and enhanced BCSCs in RANK-overexpressing cells. In contrast, in LGR4-overexpressing cells, RANKL failed to activate NF-κB but instead inhibited the Wnt/β-catenin pathway, leading to a reduction in BCSCs.

Conclusion

Our findings suggest that RANKL exerts different responses according to the expression of its receptors.

背景：乳腺癌干细胞（BCSC）是一个负责癌症抵抗和复发的亚群。核因子κ κ -Β配体受体激活因子（RANKL）是一种能够激活RANK和LGR4受体的细胞因子。RANKL/RANK信号维持BCSCs的自我更新，然而，RANKL通过LGR4的作用尚不清楚。来自破骨细胞的证据表明，RANKL/LGR4轴破坏RANK信号，导致相反的细胞反应。抗RANKL抑制剂是清除CSCs的潜在药物，但其对RANKL/LGR4信号的影响尚未得到证实。目的：本项目旨在阐明RANKL通过其受体的表达调控干细胞的作用。方法：采用体外和体内两种方法，对低表达或高表达lgr4的细胞进行RANKL抑制对干细胞的影响。此外，我们分析了RANKL刺激对LGR4或RANK过表达细胞的干性的影响。此外，我们评估了RANKL/LGR4信号通路对Wnt/β-catenin和NF-κB信号通路活性的影响。结果：我们的研究结果表明，在高LGR4水平的患者中，RANKL表达升高与良好的预后有关。此外，RANKL抑制降低了lgr4低的细胞系的BCSC特性，而促进了lgr4高的细胞的迁移。此外，RANKL/RANK轴激活NF-κB信号通路，并在RANK过表达的细胞中增强BCSCs。相比之下，在lgr4过表达的细胞中，RANKL不能激活NF-κB，而是抑制Wnt/β-catenin通路，导致BCSCs减少。结论：RANKL根据其受体的表达而产生不同的反应。

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引用次数: 0

GATA3: Orchestrating cellular fate through differentiation and proliferation GATA3：通过分化和增殖协调细胞命运。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119893

Rim Bacha , Shona Pedersen , Rana Ismail , Nouran Alwisi , Layla Al-Mansoori

Cell proliferation and differentiation are two fundamental biological processes that occur in biological systems, tightly regulated by various factors such as transcription factors (TFs). Zinc finger proteins are TFs responsible for maintaining the biological balance via coordinating development and functionality within the living cells. GATA binding protein 3 (GATA3), one of the zinc finger proteins, plays an essential role in driving differentiation and proliferation-related processes, thereby contributing to the regulation of the dynamism and productivity of living cells. By elucidating the complex interactions governed by GATA3, this underscores its significance in maintaining cellular homeostasis. Thus, the current review delves into the molecular pathways influenced by GATA3, highlighting its involvement in multiple developmental processes of various tissues and body sites, particularly in the hematopoietic system (T-cell differentiation), neural tissue differentiation, adipose tissue, as well as epithelial cell maturation.

细胞增殖和分化是发生在生物系统中的两个基本生物学过程，受到转录因子等多种因素的严格调控。锌指蛋白是通过协调活细胞内的发育和功能来维持生物平衡的tf。GATA结合蛋白3 （GATA binding protein 3, GATA3）是锌指蛋白之一，在细胞分化和增殖相关过程中发挥重要作用，对细胞的活力和生产力具有调节作用。通过阐明GATA3控制的复杂相互作用，这强调了它在维持细胞稳态中的重要性。因此，本综述深入探讨了受GATA3影响的分子途径，强调其参与多种组织和身体部位的多种发育过程，特别是造血系统（t细胞分化）、神经组织分化、脂肪组织以及上皮细胞成熟。

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引用次数: 0

Dedicator of cytokinesis protein 2 activates the epithelial–mesenchymal transition in renal fibrosis through the Rac1/PI3K/AKT pathway 细胞分裂献身蛋白2通过Rac1/PI3K/AKT通路激活肾纤维化的上皮-间质转化。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119894

Yuanyuan Jia , Jing Sun , Sha Chen , Yu Bian , Anni Jiang , Haihai Liang , Xuanyi Du

Renal fibrosis is the most important feature of the progression of chronic kidney disease (CKD), and epithelial–mesenchymal transition (EMT) plays an important role in renal fibrosis. Dedicator of cytokinesis protein 2 (Dock2) is involved in the immune system and the development of a variety of fibrotic diseases. However, its specific role in renal fibrosis remains unclear. Therefore, in this study, we investigated the role and mechanism of Dock2 in renal fibrosis. We constructed an in vivo mouse model of unilateral ureteral obstruction (UUO) and an in vitro model of recombinant human transforming growth factor-β1 (TGF-β1)-induced HK-2 cells. The function and regulatory mechanism of Dock2 were studied via Western blotting, qRT-PCR, immunohistochemistry and immunofluorescence. First, Dock2 was more highly expressed in the kidneys of UUO mice than in those of sham-operated mice. A reduction in Dock2 can improve pathological changes in the kidney tissue of UUO mice, reduce the deposition of the extracellular matrix (ECM), and alleviate EMT. Silencing Dock2 reduced the activation of both the Rac1 pathway and the PI3K/AKT pathway. TGF-β1 promoted Dock2 expression in HK-2 cells in vitro. A decrease in Dock2 can inhibit the expression of Fibronectin, Collagen I, α-SMA and Vimentin and increase the level of E-cadherin. Treatment of HK-2 cells with the Rac1 activator 8-CPT or the PI3K/AKT pathway activator YS-49 inhibited the above changes induced by siDock2, indicating that Dock2 activates EMT in renal fibrosis through the Rac1/PI3K/AKT pathway. Our data suggest that Dock2 may be a potential target for renal fibrosis treatment.

肾纤维化是慢性肾病（CKD）进展的最重要特征，上皮间质转化（epithelial-mesenchymal transition， EMT）在肾纤维化中起重要作用。细胞分裂献身蛋白2 （Dock2）参与免疫系统和多种纤维化疾病的发展。然而，其在肾纤维化中的具体作用尚不清楚。因此，在本研究中，我们研究了Dock2在肾纤维化中的作用和机制。建立小鼠单侧输尿管梗阻（UUO）体内模型和重组人转化生长因子-β1 （TGF-β1）诱导HK-2细胞体外模型。采用Western blotting、qRT-PCR、免疫组织化学和免疫荧光等方法研究Dock2的功能和调控机制。首先，Dock2在UUO小鼠肾脏中的表达高于假手术小鼠。Dock2的减少可以改善UUO小鼠肾组织的病理改变，减少细胞外基质（ECM）的沉积，减轻EMT。沉默Dock2降低了Rac1通路和PI3K/AKT通路的激活。TGF-β1在体外促进HK-2细胞Dock2的表达。Dock2降低可抑制纤维连接蛋白、I型胶原、α-SMA和Vimentin的表达，升高E-cadherin的水平。用Rac1激活剂8-CPT或PI3K/AKT通路激活剂YS-49处理HK-2细胞可抑制siDock2诱导的上述变化，表明Dock2通过Rac1/PI3K/AKT通路激活肾纤维化中的EMT。我们的数据表明Dock2可能是肾纤维化治疗的潜在靶点。

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引用次数: 0

Vasoactive intestinal peptide induces metabolic rewiring of human-derived cytotrophoblast cells to promote cell migration 血管活性肠肽诱导人源性细胞滋养层细胞代谢重组，促进细胞迁移。

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-02-01 DOI: 10.1016/j.bbamcr.2024.119886

Fátima Merech, Brenda Lara, Daiana Rios, Daniel Paparini, Rosanna Ramhorst, Vanesa Hauk, Claudia Pérez Leirós , Daiana Vota

The placenta has an extraordinary metabolic rate with high oxygen consumption. Extravillous cytotrophoblast cells (EVT) metabolism and function are critical to sustain their invasive phenotype supporting fetal development. Deficient EVT function underlies pregnancy complications as preeclampsia (PE) and fetal growth restriction (FGR). The vasoactive intestinal peptide (VIP) promotes human cytotrophoblast cell migration and invasion through mTOR signaling pathways suggesting its crucial role during placentation. Here we explored fatty acid uptake as well as lipid and glucose metabolism in human-derived cytotrophoblast cell function upon VIP stimulation. We found that VIP induced long chain fatty acid (LCFAs) uptake along with the expression of FATP2 transporter, CPT1 fatty acid oxidation (FAO)-rate limiting step importer, and lipid droplet accumulation. VIP induced the expression of glucose 6-P-dehydrogenase, a rate-limiting enzyme of the pentose phosphate pathway (PPP) and pyruvate dehydrogenase complex enzyme DLAT E2, without altering lactate secretion. This metabolic rewiring of trophoblast cells induced by VIP takes place without compromising mitochondrial function or reactive oxygen species (ROS) production. Moreover, cytotrophoblast cell migration induced by VIP required the three glycolysis, oxidative phosphorylation (OXPHOS) and FAO pathways. Our results provide evidence supporting VIP as a metabolic regulatory peptide in cytotrophoblast cells sustaining proper placentation and fetal growth.

胎盘的代谢率非常高，耗氧量也很高。体外细胞滋养层细胞（EVT）的代谢和功能是维持其侵袭性表型支持胎儿发育的关键。EVT功能缺陷是妊娠并发症如先兆子痫（PE）和胎儿生长受限（FGR）的基础。血管活性肠肽（VIP）通过mTOR信号通路促进人细胞滋养层细胞迁移和侵袭，提示其在胎盘形成过程中起重要作用。本研究探讨了VIP刺激对人源性细胞滋养层细胞功能的脂肪酸摄取、脂质和糖代谢的影响。我们发现VIP诱导长链脂肪酸（LCFAs）摄取，同时表达FATP2转运蛋白、CPT1脂肪酸氧化（FAO）速率限制步骤入口蛋白和脂滴积累。VIP诱导葡萄糖6- p -脱氢酶（戊糖磷酸途径的限速酶）和丙酮酸脱氢酶复合物DLAT E2的表达，但不改变乳酸分泌。这种由VIP诱导的滋养细胞的代谢重新布线在不影响线粒体功能或活性氧（ROS）产生的情况下发生。此外，VIP诱导的细胞滋养层细胞迁移需要糖酵解、氧化磷酸化（OXPHOS）和FAO三种途径。我们的研究结果提供了支持VIP作为细胞滋养层细胞维持正常胎盘和胎儿生长的代谢调节肽的证据。

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