Molecular and Cellular Biology最新文献_第4页

Liver Receptor Homolog-1 Deficiency Impairs Alcohol-Associated Liver Disease Owing to Decrease of Aldehyde Dehydrogenase 1 Family Member B1 Gene Expression. 由于醛脱氢酶1家族成员B1基因表达减少，肝脏受体同源物-1缺乏损害酒精相关性肝病

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-25 DOI: 10.1080/10985549.2025.2505729

Min-Hee Seo, Jae-Ho Lee, Eun-Ho Lee, Sulagna Mukherjee, Soo-Young Park, Jae-Hoon Bae, Dae-Kyu Song, Seung-Soon Im

{"title":"Liver Receptor Homolog-1 Deficiency Impairs Alcohol-Associated Liver Disease Owing to Decrease of Aldehyde Dehydrogenase 1 Family Member B1 Gene Expression.","authors":"Min-Hee Seo, Jae-Ho Lee, Eun-Ho Lee, Sulagna Mukherjee, Soo-Young Park, Jae-Hoon Bae, Dae-Kyu Song, Seung-Soon Im","doi":"10.1080/10985549.2025.2505729","DOIUrl":"10.1080/10985549.2025.2505729","url":null,"abstract":"Ethanol is detoxified in the liver, and its intake causes hepatic lipid accumulation. The liver receptor homolog-1 (LRH-1) regulates lipid and bile acid metabolism, but its role in ethanol metabolism remains unclear. This study aimed to explore the relationship between ethanol-induced lipid accumulation and LRH-1. To investigate the role of LRH-1 in hepatic ethanol metabolism, LRH-1f/f and liver-specific LRH-1f/cre+ mice were fed a Lieber-DeCarli diet for 3 weeks. The results showed that ethanol-fed LRH-1f/cre+ mice exhibited increased neutral fat, total cholesterol, liver damage markers, and acetaldehyde levels. Moreover, ethanol-fed LRH-1f/cre+ mice displayed decreased fatty acid oxidation, impaired mitochondrial function, and increased reactive oxygen species levels. To identify LRH-1 targets in ethanol metabolism, RNA sequencing analysis revealed significant changes in genes involved in fatty acid metabolism between the control and ethanol groups. Notably, in the absence of LRH-1, ethanol metabolism genes showed a reduction in aldehyde dehydrogenase 1 family member b1 (ALDH1B1) expression. Furthermore, LRH-1 overexpression in HepG2 cells led to increased ALDH1B1 expression, and ChIP sequencing data confirmed the LRH-1 binding peaks in the ALDH1B1 promoter region. In conclusion, this study confirms that LRH-1 depletion results in decreased ALDH1B1 expression, leading to acetaldehyde accumulation and accelerated intrahepatic fat accumulation.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"301-314"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142913","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

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

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 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub 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":"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":"225-237"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12317676/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

acp³U: A Conserved RNA Modification with Lessons Yet to Unfold. acp³U：一个保守的RNA修饰与教训尚未展开。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-01-06 DOI: 10.1080/10985549.2024.2443138

Mariana D Mandler, Sneha Kulkarni, Pedro J Batista

引用次数: 0

Elevated Type I Interferon Signaling Defines the Proliferative Advantage of ARF and p53 Mutant Tumor Cells. I型干扰素信号的升高决定了ARF和p53突变肿瘤细胞的增殖优势。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-12 DOI: 10.1080/10985549.2025.2497817

Alex Mabry, Catherine E Kuzmicki, Angelina O'Brien, Leonard B Maggi, Jason D Weber

{"title":"Elevated Type I Interferon Signaling Defines the Proliferative Advantage of ARF and p53 Mutant Tumor Cells.","authors":"Alex Mabry, Catherine E Kuzmicki, Angelina O'Brien, Leonard B Maggi, Jason D Weber","doi":"10.1080/10985549.2025.2497817","DOIUrl":"10.1080/10985549.2025.2497817","url":null,"abstract":"The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massive gains in cell proliferation and transformation and is often observed in some of the most aggressive human cancer subtypes. These phenotypic gains are preceded by increased type I interferon (IFN) signaling that involves canonical STAT1 activation and a subsequent IFN-stimulated gene (ISG) signature. Here, we show that cells lacking p53 and ARF require active JAK1 to phosphorylate STAT1 on Y701 to maintain their high rate of proliferation. In fact, the use of selective JAK1 inhibitors ruxolitinib or baricitinib inhibited the induction of ISG's and the proliferation of p53 and ARF deleted cells. We identify a group of solid human tumors that lack functional p53 and ARF, show an expression signature of the upregulated type I IFN response genes, and are sensitive to selective JAK1 inhibitors. These data suggest that the type I IFN response acts as a positive driver of proliferation in the absence of p53 and ARF and, as such, presents itself as a potential therapeutic target in aggressive solid tumors.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"246-261"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12136988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017892","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

miR-365-3p Regulates Gastrointestinal Dysfunction in Diabetes Mellitus Rats via the TLR4/MyD88/NF-κB Pathway. miR-365-3p通过TLR4/MyD88/NF-κB通路调控糖尿病大鼠胃肠道功能障碍

IF 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-07-22 DOI: 10.1080/10985549.2025.2532581

Jiao Xiao, Bin Gao, Yan Xiao, Xiangjie Liu

{"title":"miR-365-3p Regulates Gastrointestinal Dysfunction in Diabetes Mellitus Rats via the TLR4/MyD88/NF-κB Pathway.","authors":"Jiao Xiao, Bin Gao, Yan Xiao, Xiangjie Liu","doi":"10.1080/10985549.2025.2532581","DOIUrl":"10.1080/10985549.2025.2532581","url":null,"abstract":"Over half of diabetes mellitus (DM) patients suffer from gastrointestinal motility disorders. miR-365-3p is involved in DM progression, but its role in gastrointestinal motility disorders remains unclear. This study explored whether miR-365-3p affects gastrointestinal motility in diabetic rats via the TLR4/MyD88/NF-κB pathway. A DM rat model was established using a high-fat, high-sugar diet and injected with a miR-365-3p mimic/inhibitor. DM symptoms, gastric emptying, intestinal propulsion rates, and gastrointestinal transit time were assessed. HE and TUNEL staining evaluated gastrointestinal pathology and apoptosis. qRT-PCR detected miR-365-3p levels, while ELISA assessed gastrointestinal motility-related factors. Immunofluorescence and Western blot analyzed C-kit, TLR4, and pathway proteins. DM rats exhibited increased body weight, blood glucose, and glucose intolerance, with reduced fasting insulin, confirming successful modeling. miR-365-3p was downregulated in DM rats. Injection of miR-365-3p mimic alleviated DM symptoms, reduced gastrointestinal tissue damage and apoptosis, and improved motility. The TLR4 agonist CRX-527 impaired these effects. In conclusion, miR-365-3p overexpression alleviates DM symptoms, gastrointestinal injury, and motility disorders by inhibiting the TLR4/MyD88/NF-κB pathway, offering a potential therapeutic target.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"438-454"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682807","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

Identification of a Novel Intracellular Function of the Secreted Ribonuclease RNASE1 in Inhibiting Gene Expression. 分泌核糖核酸酶RNASE1在抑制基因表达中的细胞内新功能的鉴定。

IF 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-06-17 DOI: 10.1080/10985549.2025.2504972

Ragini Singh, Ahlina Archibald, Xiao Ling Li, Ravi Kumar, Shaoli Das, Erica C Pehrsson, Patrick X Zhao, Xinyu Wen, Raj Chari, Ioannis Grammatikakis, Ashish Lal

{"title":"Identification of a Novel Intracellular Function of the Secreted Ribonuclease RNASE1 in Inhibiting Gene Expression.","authors":"Ragini Singh, Ahlina Archibald, Xiao Ling Li, Ravi Kumar, Shaoli Das, Erica C Pehrsson, Patrick X Zhao, Xinyu Wen, Raj Chari, Ioannis Grammatikakis, Ashish Lal","doi":"10.1080/10985549.2025.2504972","DOIUrl":"10.1080/10985549.2025.2504972","url":null,"abstract":"RNASE1 is a ribonuclease secreted by cells and degrades extracellular RNAs. Here, we unexpectedly found that RNASE1, in addition to being secreted, is predominantly localized to the nucleus and functions to inhibit gene expression in human colorectal cancer (CRC) cells. RNASE1 expression is highly cell type-specific and is restricted to well-differentiated CRC cells where its transcription is activated by the pioneer transcription factor FOXA1. Using CRISPR interference utilizing three independent sgRNAs targeting the RNASE1 locus followed by RNA-seq, we found that upon depletion of RNASE1, most of the differentially expressed RNAs are modestly but significantly upregulated suggesting that RNASE1 predominantly functions to inhibit gene expression. In CRC patients, RNASE1 is significantly downregulated and high RNASE1 expression is associated with better patient survival, indicating a potential tumor suppressive function. Consistent with this, RNASE1 depletion results in increased proliferation and clonogenicity indicating that RNASE1 inhibits the growth of CRC cells. Finally, a promising RNASE1 target among the most significantly upregulated mRNAs upon RNASE1 depletion is DKK1 (Dickkopf inhibitor 1) which is upregulated in CRC and negatively regulated by RNASE1. Collectively, this initial characterization of endogenous RNASE1 uncovers a function of RNASE1 in inhibition of gene expression and CRC cell proliferation.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"315-326"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12316042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144317469","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

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

The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors. 泛素E3连接酶UBE3A调控与AMPA受体内吞循环相关的GRIPAP1和PACSIN1蛋白。

IF 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-07-16 DOI: 10.1080/10985549.2025.2470431

Laura Drebushenko, Natalya Belous, Fritz W Lischka, Qiong Zhou, Ayse Malci, Michael S Sidorov, Barrington Burnett, Martin L Doughty

{"title":"The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors.","authors":"Laura Drebushenko, Natalya Belous, Fritz W Lischka, Qiong Zhou, Ayse Malci, Michael S Sidorov, Barrington Burnett, Martin L Doughty","doi":"10.1080/10985549.2025.2470431","DOIUrl":"10.1080/10985549.2025.2470431","url":null,"abstract":"Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive and language impairments, seizures, reduced or fragmented sleep, motor ataxia, and a characteristic happy affect. AS arises due to the neuronal loss of UBE3A, an E3 ligase that regulates protein abundance through the addition of lysine 48 (K48)-linked polyubiquitin chains to proteins targeted for degradation by the ubiquitin proteasome system (UPS). Using a dual SMAD inhibition protocol to derive cortical neurons from human induced pluripotent stem cells, we examined UBE3A deletion effects on the neuronal proteome by liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS identified 645 proteins differentially abundant between UBE3A knockout (KO) and isogenic UBE3A wild-type control cortical neurons. Proteins with increased abundance with UBE3A loss of function include GRIPAP1 and PACSIN1, synaptic proteins implicated in AMPA receptor recycling. We provide evidence UBE3A polyubiquitinates PACSIN1 and GRIPAP1 to regulate protein turnover, with potential implications for impaired activity-dependent synaptic plasticity observed in AS.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"353-368"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649814","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