Molecular and Cellular Biology最新文献_第2页

Mitogen-Activated Protein Kinase Phosphatase-5 is Required for TGF-β Signaling Through a JNK-Dependent Pathway. 丝裂原活化蛋白激酶磷酸酶-5 是通过 JNK 依赖性途径传递 TGF-β 信号的必要条件

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-11-28 DOI: 10.1080/10985549.2024.2426665

Sam Dorry, Sravan Perla, Anton M Bennett

{"title":"Mitogen-Activated Protein Kinase Phosphatase-5 is Required for TGF-β Signaling Through a JNK-Dependent Pathway.","authors":"Sam Dorry, Sravan Perla, Anton M Bennett","doi":"10.1080/10985549.2024.2426665","DOIUrl":"10.1080/10985549.2024.2426665","url":null,"abstract":"Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute members of the dual-specificity family of protein phosphatases that dephosphorylate the MAPKs. MKP-5 dephosphorylates the stress-responsive MAPKs, p38 MAPK and JNK, and has been shown to promote tissue fibrosis. Here, we provide insight into how MKP-5 regulates the transforming growth factor-β (TGF-β) pathway, a well-established driver of fibrosis. We show that MKP-5-deficient fibroblasts in response to TGF-β are impaired in SMAD2 phosphorylation at canonical and non-canonical sites, nuclear translocation, and transcriptional activation of fibrogenic genes. Consistent with this, pharmacological inhibition of MKP-5 is sufficient to block TGF-β signaling, and that this regulation occurs through a JNK-dependent pathway. By utilizing RNA sequencing and transcriptomic analysis, we identify TGF-β signaling activators regulated by MKP-5 in a JNK-dependent manner, providing mechanistic insight into how MKP-5 promotes TGF-β signaling. This study elucidates a novel mechanism whereby MKP-5-mediated JNK inactivation is required for TGF-β signaling and provides insight into the role of MKP-5 in tissue fibrosis.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"17-31"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11693473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739859","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

The Role of Med15 Sequence Features in Transcription Factor Interactions. Med15序列特征在转录因子相互作用中的作用

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-12-24 DOI: 10.1080/10985549.2024.2436672

David G Cooper, Shulin Liu, Emma Grunkemeyer, Jan S Fassler

{"title":"The Role of Med15 Sequence Features in Transcription Factor Interactions.","authors":"David G Cooper, Shulin Liu, Emma Grunkemeyer, Jan S Fassler","doi":"10.1080/10985549.2024.2436672","DOIUrl":"10.1080/10985549.2024.2436672","url":null,"abstract":"Med15 is a general transcriptional regulator and tail module subunit within the RNA Pol II mediator complex. The Saccharomyces cerevisiae Med15 protein has a well-structured N-terminal KIX domain, three activator binding domains (ABDs) and several naturally variable polyglutamine (poly-Q) tracts (Q1, Q2, Q3) embedded in an intrinsically disordered central region, and a C-terminal mediator association domain (MAD). We investigated how the presence of ABDs and changes in length and composition of poly-Q tracts influences Med15 activity using phenotypic, gene expression, transcription factor interaction and phase separation assays of truncation, deletion, and synthetic alleles. We found that individual Med15 activities were influenced by the number of activator binding domains (ABDs) and adjacent polyglutamine tract composition. Robust Med15 activity required at least the Q1 tract and the length of that tract modulated activity in a context-dependent manner. Reduced Msn2-dependent transcriptional activation due to Med15 Q1 tract variation correlated with reduced Msn2:Med15 interaction strength, but interaction strength did not always mirror phase separation propensity. We also observed that distant glutamine tracts and Med15 phosphorylation affected the activities of the KIX domain, and interaction studies revealed that intramolecular interactions may affect some Med15-transcription factor interactions.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"59-78"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882539","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

Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma. c19位置取代格尔达霉素衍生物靶向nrf2 - nqo1激活的食管鳞状细胞癌的抗癌作用

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-12-24 DOI: 10.1080/10985549.2024.2438817

Hiroyuki Oshikiri, Keiko Taguchi, Wataru Hirose, Yusuke Taniyama, Takashi Kamei, David Siegel, David Ross, Russell R A Kitson, Liam Baird, Masayuki Yamamoto

{"title":"Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma.","authors":"Hiroyuki Oshikiri, Keiko Taguchi, Wataru Hirose, Yusuke Taniyama, Takashi Kamei, David Siegel, David Ross, Russell R A Kitson, Liam Baird, Masayuki Yamamoto","doi":"10.1080/10985549.2024.2438817","DOIUrl":"10.1080/10985549.2024.2438817","url":null,"abstract":"In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"79-97"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882538","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

Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1. 小分子筛选发现 HSP90 是肌营养不良症 1 型 RNA 病灶的修饰因子

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-10-17 DOI: 10.1080/10985549.2024.2408025

Sara J Johnson, Hannah L Johnson, Reid T Powell, Clifford Stephan, Fabio Stossi, Thomas A Cooper

{"title":"Small Molecule Screening Identifies HSP90 as a Modifier of RNA Foci in Myotonic Dystrophy Type 1.","authors":"Sara J Johnson, Hannah L Johnson, Reid T Powell, Clifford Stephan, Fabio Stossi, Thomas A Cooper","doi":"10.1080/10985549.2024.2408025","DOIUrl":"https://doi.org/10.1080/10985549.2024.2408025","url":null,"abstract":"Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG triplet repeat expansion within the 3' untranslated region of the DMPK gene. Expression of the expanded allele generates RNA containing long tracts of CUG repeats (CUGexp RNA) that form hairpin structures and accumulate in nuclear RNA foci; however, the factors that control DMPK expression and the formation of CUGexp RNA foci remain largely unknown. We performed an unbiased small molecule screen in an immortalized human DM1 skeletal muscle myoblast cell line and identified HSP90 as a modifier of endogenous RNA foci. Small molecule inhibition of HSP90 leads to enhancement of RNA foci and upregulation of DMPK mRNA levels. Knockdown and overexpression of HSP90 in undifferentiated DM1 myoblasts validated the impact of HSP90 with upregulation and downregulation of DMPK mRNA, respectively. Furthermore, we identified p-STAT3 as a downstream mediator of HSP90 impacting levels of DMPK mRNA and RNA foci. Interestingly, differentiated cells exhibited an opposite effect of HSP90 inhibition displaying downregulation of DMPK mRNA through a mechanism independent of p-STAT3 involvement. This study has revealed a novel mediator for DMPK mRNA and foci regulation in DM1 cells with the potential to identify targets for future therapeutic intervention.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"1-13"},"PeriodicalIF":3.2,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470011","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

Midnolin, a Genetic Risk Factor for Parkinson’s Disease, Promotes Neurite Outgrowth Accompanied by Early Growth Response 1 Activation in PC12 Cells 帕金森病的遗传风险因子 Midnolin 能促进 PC12 细胞中神经元的生长，同时激活早期生长应答 1

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2024-09-12 DOI: 10.1080/10985549.2024.2399358

Ayano Chiba Chisato Kato Tadashi Nakagawa Tsukasa Osaki Kohei Nakamura Ikuo Norota Mikako Nagashima Toru Hosoi Kuniaki Ishii Yutaro Obara a Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japanb Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo Onoda, Japanc Department of Biochemistry and Molecular Biology, Yamagata University School of Medicine, Yamagata, Japan

引用次数: 0

Statement of Retraction: FLIP Protects against Hypoxia/Reoxygenation-Induced Endothelial Cell Apoptosis by Inhibiting Bax Activation. 撤回声明：FLIP通过抑制Bax活化防止缺氧/再氧诱导的内皮细胞凋亡

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-09-03 DOI: 10.1080/10985549.2024.2396764

引用次数: 0

Selective Hypoxia-Sensitive Oxomer Formation by FIH Prevents Binding of the NF-κB Inhibitor IκBβ to NF-κB Subunits FIH选择性缺氧敏感氧化物形成可阻止NF-κB抑制剂IκBβ与NF-κB亚基结合

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2024-04-22 DOI: 10.1080/10985549.2024.2338727

Yulia L. VolkovaAgnieszka E. JuchtNina OechslerRoopesh KrishnankuttyAlex von KriegsheimRoland H. WengerCarsten C. Scholza Institute of Physiology, University of Zurich, Zurich, Switzerlandb Institute of Physiology, University Medicine Greifswald, Greifswald, Germanyc Institute of Genetics and Cancer, University of Edinburgh, UK

引用次数: 0

Endogenous EWSR1 Exists in Two Visual Modalities That Reflect Its Associations with Nucleic Acids and Concentration at Sites of Active Transcription 内源性 EWSR1 存在于两种视觉模式，反映了它与核酸的关联以及在活性转录位点的浓度

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2024-03-20 DOI: 10.1080/10985549.2024.2315425

Soumya Sundara RajanVernon J. EbegboniPatricio PichlingKatelyn R. LudwigTamara L. JonesRaj ChariAndy TranMichael J. KruhlakJadranka LoncarekNatasha J. Caplena Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAb Genome Modification Core, Laboratory Animal Sciences Program, Frederick National Lab for Cancer Research, Frederick, Maryland, USAc CCR Confocal Microscopy Core Facility, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USAd Centrosome Biology Section, Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA

引用次数: 0

Uncovering the Role of the Yeast Lysine Acetyltransferase NuA4 in the Regulation of Nuclear Shape and Lipid Metabolism. 揭示酵母赖氨酸乙酰转移酶 NuA4 在核形状和脂质代谢调控中的作用

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-01-01 Epub Date: 2024-07-04 DOI: 10.1080/10985549.2024.2366206

Sarah Jane Laframboise, Lauren F Deneault, Alix Denoncourt, Michael Downey, Kristin Baetz

{"title":"Uncovering the Role of the Yeast Lysine Acetyltransferase NuA4 in the Regulation of Nuclear Shape and Lipid Metabolism.","authors":"Sarah Jane Laframboise, Lauren F Deneault, Alix Denoncourt, Michael Downey, Kristin Baetz","doi":"10.1080/10985549.2024.2366206","DOIUrl":"10.1080/10985549.2024.2366206","url":null,"abstract":"Here, we report a novel role for the yeast lysine acetyltransferase NuA4 in regulating phospholipid availability for organelle morphology. Disruption of the NuA4 complex results in 70% of cells displaying nuclear deformations and nearly 50% of cells exhibiting vacuolar fragmentation. Cells deficient in NuA4 also show severe defects in the formation of nuclear-vacuole junctions (NJV), as well as a decrease in piecemeal microautophagy of the nucleus (PMN). To determine the cause of these defects we focused on Pah1, an enzyme that converts phosphatidic acid into diacylglycerol, favoring accumulation of lipid droplets over phospholipids that are used for membrane expansion. NuA4 subunit Eaf1 was required for Pah1 localization to the inner nuclear membrane and artificially tethering of Pah1 to the nuclear membrane rescued nuclear deformation and vacuole fragmentation defects, but not defects related to the formation of NVJs. Mutation of a NuA4-dependent acetylation site on Pah1 also resulted in aberrant Pah1 localization and defects in nuclear morphology and NVJ. Our work suggests a critical role for NuA4 in organelle morphology that is partially mediated through the regulation of Pah1 subcellular localization.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"273-288"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11253884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498377","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

Unveiling the Role of Sik1 in Osteoblast Differentiation: Implications for Osteoarthritis. 揭示 Sik1 在成骨细胞分化中的作用：对骨关节炎的影响

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-01-01 Epub Date: 2024-08-22 DOI: 10.1080/10985549.2024.2385633

Kuanmin Tian, Xiaoxin He, Xue Lin, Xiaolei Chen, Yajing Su, Zhidong Lu, Zhirong Chen, Liang Zhang, Peng Li, Long Ma, Zhibin Lan, Xin Zhao, Gangning Fen, Qinqin Hai, Di Xue, Qunhua Jin

{"title":"Unveiling the Role of Sik1 in Osteoblast Differentiation: Implications for Osteoarthritis.","authors":"Kuanmin Tian, Xiaoxin He, Xue Lin, Xiaolei Chen, Yajing Su, Zhidong Lu, Zhirong Chen, Liang Zhang, Peng Li, Long Ma, Zhibin Lan, Xin Zhao, Gangning Fen, Qinqin Hai, Di Xue, Qunhua Jin","doi":"10.1080/10985549.2024.2385633","DOIUrl":"10.1080/10985549.2024.2385633","url":null,"abstract":"Osteoarthritis (OA) is a chronic degenerative disease characterized by subchondral osteosclerosis, mainly due to osteoblast activity. This research investigates the function of Sik1, a member of the AMP-activated protein kinase family, in OA. Proteomic analysis was conducted on clinical samples from 30 OA patients, revealing a negative correlation between Sik1 expression and OA. In vitro experiments utilized BMSCs to examine the effect of Sik1 on osteogenic differentiation. BMSCs were cultured and induced toward osteogenesis with specific media. Sik1 overexpression was achieved through lentiviral transfection, followed by analysis of osteogenesis-associated proteins using Western blotting, RT-qPCR, and alkaline phosphate staining. In vivo experiments involved destabilizing the medial meniscus in mice to establish an OA model, assessing the therapeutic potential of Sik1. The CT scans and histological staining were used to analyze subchondral bone alterations and cartilage damage. The findings show that Sik1 downregulation correlates with advanced OA and heightened osteogenic differentiation in BMSCs. Sik1 overexpression inhibits osteogenesis-related markers in vitro and reduces cartilage damage and subchondral osteosclerosis in vivo. Mechanistically, Sik1 modulates osteogenesis and subchondral bone changes through Runx2 activity regulation. The research emphasizes Sik1 as a promising target for treating OA, suggesting its involvement in controlling bone formation and changes in the subchondral osteosclerosis.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"411-428"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11485870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017976","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