Molecular and Cellular Biology最新文献_第3页

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 As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione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

Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome. 转录组学分析揭示了ADNP综合征中未折叠蛋白的反应。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-02-14 DOI: 10.1080/10985549.2025.2463892

Anna Bieluszewska, Phillip Wulfridge, Kuo-Chen Fang, Yan Hong, Tomoyo Sawada, Jennifer Erwin, Hongjun Song, Guo-Li Ming, Kavitha Sarma

{"title":"Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome.","authors":"Anna Bieluszewska, Phillip Wulfridge, Kuo-Chen Fang, Yan Hong, Tomoyo Sawada, Jennifer Erwin, Hongjun Song, Guo-Li Ming, Kavitha Sarma","doi":"10.1080/10985549.2025.2463892","DOIUrl":"10.1080/10985549.2025.2463892","url":null,"abstract":"Chromatin regulators are frequently mutated in autism spectrum disorders, but in most cases how they cause disease is unclear. Mutations in the activity dependent neuroprotective protein (ADNP) causes ADNP syndrome, which is characterized by intellectual deficiency and developmental delays. To identify mechanisms that contribute to ADNP syndrome, we used induced pluripotent stem cells derived from ADNP syndrome patients as a model to test the effects of syndromic ADNP mutations on gene expression and neurodifferentiation. We found that some ADNP mutations result in truncated ADNP proteins, which displayed aberrant subcellular localization. Gene expression analyses revealed widespread transcriptional deregulation in all tested mutants. Interestingly, mutants that show presence of ADNP fragments show ER stress as evidenced by activation of the unfolded protein response (UPR). The mutants showing the greatest UPR pathway activation associated with the most severe neurodifferentiation and survival defects. Our results reveal the potential to explore UPR activation as a new biomarker for ADNP syndrome severity and perhaps also in other ASDs where mutations result in presence of truncated proteins.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"143-153"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12138805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414674","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

Protein Phosphatase 1 Regulatory Subunit PNUTS Prevents CENP-A Mislocalization and Chromosomal Instability. 蛋白磷酸酶1调控亚基PNUTS防止CENP-A错位和染色体不稳定性。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-04-24 DOI: 10.1080/10985549.2025.2487010

Vinutha Balachandra, Makenzie Thomas, Roshan L Shrestha, Subhash Chandra Sethi, Raj Chari, Shinjen Lin, Ken Chih-Chien Cheng, Tatiana S Karpova, Natasha J Caplen, Munira A Basrai

{"title":"Protein Phosphatase 1 Regulatory Subunit PNUTS Prevents CENP-A Mislocalization and Chromosomal Instability.","authors":"Vinutha Balachandra, Makenzie Thomas, Roshan L Shrestha, Subhash Chandra Sethi, Raj Chari, Shinjen Lin, Ken Chih-Chien Cheng, Tatiana S Karpova, Natasha J Caplen, Munira A Basrai","doi":"10.1080/10985549.2025.2487010","DOIUrl":"10.1080/10985549.2025.2487010","url":null,"abstract":"Chromosomal instability (CIN), a major hallmark of cancer, can be driven by defects in the integrity of centromere or kinetochore structure. Coordinated control of phosphorylation and dephosphorylation activities during cell division is critical to ensure chromosomal stability. Overexpression of the centromeric histone H3 variant CENP-A is observed in many cancers, and its mislocalization to noncentromeric regions promotes CIN. We identified protein phosphatase 1 (PP1) nuclear targeting subunit (PNUTS) as a top candidate in a genome-wide siRNA screen for gene depletions that lead to increased nuclear CENP-A levels. Here, we define a role for PNUTS in preventing CENP-A mislocalization and CIN. Depletion of PNUTS resulted in high nuclear CENP-A levels throughout the cell cycle in a PP1-dependent manner. Consistent with these results, mislocalization of CENP-A and its interacting partner CENP-C were observed on mitotic chromosomes from PNUTS-depleted cells. Defects in kinetochore integrity and CIN phenotypes were also observed in PNUTS-depleted cells. Mechanistically, we show that depletion of the histone H3.3 chaperone DAXX suppresses the mislocalization of CENP-A and micronuclei incidence in PNUTS-depleted cells. In summary, our studies highlight the importance of phospho-regulation mediated by PNUTS in preventing CENP-A mislocalization and CIN.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"185-197"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972177","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

The Ashkenazi-Centric G334R Variant of TP53 is Severely Impaired for Transactivation but Retains Tumor Suppressor Function in a Mouse Model. 在小鼠模型中，以阿什肯纳齐为中心的 TP53 G334R 变体的反式激活功能严重受损，但仍具有抑瘤功能。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2024-01-01 Epub Date: 2024-11-08 DOI: 10.1080/10985549.2024.2421885

David C Stieg, Kaitlyn Casey, Bhanu Chandra Karisetty, Julia I-Ju Leu, Fiona Larkin, Peter Vogel, Jozef Madzo, Maureen E Murphy

{"title":"The Ashkenazi-Centric G334R Variant of TP53 is Severely Impaired for Transactivation but Retains Tumor Suppressor Function in a Mouse Model.","authors":"David C Stieg, Kaitlyn Casey, Bhanu Chandra Karisetty, Julia I-Ju Leu, Fiona Larkin, Peter Vogel, Jozef Madzo, Maureen E Murphy","doi":"10.1080/10985549.2024.2421885","DOIUrl":"10.1080/10985549.2024.2421885","url":null,"abstract":"Mutations in the TP53 tumor suppressor gene are the most abundant genetic occurrences in cancer. Some of these mutations lead to loss of function of p53 protein, some are gain of function, and some variants are hypomorphic (partially functional). Currently, there is no clinical distinction between different p53 mutations and cancer therapy or prognosis. Mutations in the oligomerization domain of p53 appear to be quite distinct in function, compared to mutations in the DNA binding domain. Here we show that, like other p53 oligomerization domain mutants, the Ashkenazi-specific G334R mutant accumulates to very high levels in cells and is significantly impaired for the transactivation of canonical p53 target genes. Surprisingly, we find that this mutant retains the ability to bind to consensus p53 target sites. A mouse model reveals that mice containing the G334R variant show increased predisposition to cancer, but only a fraction of these mice develop late-onset cancer. We show that the G334R variant retains the ability to interact with the SP1 transcription factor and contributes to the transactivation of joint SP1-p53 target genes. The combined evidence indicates that G334R is a unique oligomerization domain mutant that retains some tumor suppressor function.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"607-621"},"PeriodicalIF":3.2,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624063","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