Advances in biological regulation最新文献_第2页

Afatinib alters DNA methylation and Paneth-like differentiation markers in Caco-2 cells 阿法替尼改变Caco-2细胞的DNA甲基化和panethlike分化标记

IF 2.4

Advances in biological regulation Pub Date : 2026-05-01 Epub Date: 2026-01-22 DOI: 10.1016/j.jbior.2026.101146

Ippei Uemura, Natsuko Takahashi-Suzuki, Takashi Satoh

{"title":"Afatinib alters DNA methylation and Paneth-like differentiation markers in Caco-2 cells","authors":"Ippei Uemura, Natsuko Takahashi-Suzuki, Takashi Satoh","doi":"10.1016/j.jbior.2026.101146","DOIUrl":"10.1016/j.jbior.2026.101146","url":null,"abstract":"<div><div>Afatinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used to treat EGFR-mutant non–small cell lung cancer. It frequently causes gastrointestinal toxicity that perturbs intestinal homeostasis, and its impact on Paneth-like lineage differentiation along the crypt–villus axis remains unclear. Using a controlled differentiation-stage framework in Caco-2 cells, we examined how afatinib affects Paneth-like differentiation markers. We incubated undifferentiated Caco-2 cells with afatinib (10–5000 nM) for 24 h during early culture and evaluated downstream DNA methylation and differentiation-associated readouts up to day 14. We quantified proteins (western blotting), mRNAs (RT–qPCR), and promoter methylation (methylation-sensitive restriction enzyme–qPCR). Afatinib increased DNA methylation at the SRY-box transcription factor 9 (SOX9) and defensin alpha 5 (DEFA5) promoters and reduced their protein expression. Immunostaining indicated reduced expression of Paneth-like differentiation markers in Caco-2 cells. In contrast, mRNA levels of the SOX9 regulators odd-skipped related transcription factor 1 (OSR1) and receptor-interacting protein 140 (RIP140) were upregulated without changes in promoter methylation at the analyzed sites, indicating DNA methylation–independent regulation at these promoters. These findings suggest that DNMT1/3B-skewed methylation at the SOX9/DEFA5 promoters may be counteracted by ten-eleven translocation–mediated counter-demethylation. Collectively, our data indicate that afatinib modulates Paneth-like differentiation markers via DNA methylation–dependent repression of SOX9/DEFA5 and DNA methylation–independent induction of OSR1/RIP140 in Caco-2 cells, which may be relevant to crypt-associated epithelial function and gastrointestinal safety.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"100 ","pages":"Article 101146"},"PeriodicalIF":2.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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From stress to homeostasis: Mass spectrometry–based insights into the unfolded protein response (UPR) and proteostasis 从压力到体内平衡：基于质谱的未折叠蛋白反应（UPR）和蛋白质平衡的见解。

IF 2.4

Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2025-10-30 DOI: 10.1016/j.jbior.2025.101127

Lea A. Barny , Lars Plate

{"title":"From stress to homeostasis: Mass spectrometry–based insights into the unfolded protein response (UPR) and proteostasis","authors":"Lea A. Barny , Lars Plate","doi":"10.1016/j.jbior.2025.101127","DOIUrl":"10.1016/j.jbior.2025.101127","url":null,"abstract":"<div><div>The unfolded protein response (UPR) is a central regulator of proteostasis, coordinating cellular adaptation to endoplasmic reticulum (ER) stress. It is comprised of three signaling branches: ATF6 (activating transcription factor 6), IRE1 (inositol-requiring enzyme 1), and PERK (protein kinase RNA-like ER kinase), which mediate transcriptional and translational reprogramming of the proteostasis network. These pathways display both functional redundancy and branch-specific activities. Dysregulated UPR signaling contributes to diverse pathologies: in cancer, UPR activation supports uncontrolled proliferation and treatment resistance, whereas in aging, proteostasis decline and diminished UPR responsiveness are hallmarks. Traditional approaches, including transcriptomics and western blotting, have been widely used to monitor UPR activity, but they offer limited insight into its regulation at the protein level. In contrast, liquid chromatography–tandem mass spectrometry (LC-MS/MS) based proteomics allows comprehensive, branch-specific profiling of UPR signaling. Recent advances, including data-independent acquisition (DIA) MS and automated sample preparation, have further improved sensitivity, reproducibility, and detection of low-abundance UPR target proteins. Proteomics thus provides a systematic and scalable framework to interrogate UPR regulation across cell types and disease models. When integrated with complementary datasets, protein-level measurements can uncover context-dependent molecular signatures of UPR activity, offering insights into disease mechanisms and guiding the rational design of targeted pharmacological interventions. Future work integrating high-resolution LC-MS/MS proteomics with tissue and single-cell analyses will further clarify the role of the UPR in health and disease.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101127"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145562361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Pharmacological SHIP2 blockade enhances sensitivity to standard and targeted cancer therapies 药理学SHIP2阻断增强对标准和靶向癌症治疗的敏感性。

IF 2.4

Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.jbior.2025.101130

Nadia Gillet, Cyril Bodart, Benjamin Beck

{"title":"Pharmacological SHIP2 blockade enhances sensitivity to standard and targeted cancer therapies","authors":"Nadia Gillet, Cyril Bodart, Benjamin Beck","doi":"10.1016/j.jbior.2025.101130","DOIUrl":"10.1016/j.jbior.2025.101130","url":null,"abstract":"<div><div>Esophageal squamous cell carcinoma (eSCC) is an aggressive malignancy with poor prognosis and limited therapeutic options. The phosphoinositide 3-kinase (PI3K)/AKT pathway is frequently activated in eSCC, but clinical use of PI3K or AKT inhibitors is restricted by toxicity and compensatory signaling. SHIP2, an inositol 5-phosphatase encoded by <em>INPPL1</em>, modulates this pathway by converting PI(3,4,5)P<sub>3</sub> to PI(3,4)P<sub>2</sub>, thereby regulating AKT activation. We previously identified <em>INPPL1</em> amplification as recurrent in eSCC and demonstrated that SHIP2 inhibition suppresses tumor growth and synergizes with PLK1 inhibition.</div><div>Here, we extend these findings and show that SHIP2–PLK1 synergy is not confined to eSCC but is also observed in multiple colorectal cancer cell lines, revealing a conserved vulnerability across tumor types. Mechanistic analyses demonstrate that this synergy depends on PI3K/AKT signaling, with SHIP2 inhibition producing stronger effects than direct PI3K blockade, suggesting additional regulatory functions beyond canonical PI3K control. Furthermore, SHIP2 inhibition enhances the cytotoxic activity of standard chemotherapies, including 5-fluorouracil and paclitaxel, in eSCC cells. Importantly, these effects occur at sub-cytotoxic drug concentrations, indicating potential therapeutic benefit with reduced toxicity.</div><div>Collectively, our results identify SHIP2 as a central regulator of the PI3K/AKT axis in eSCC and colorectal cancer and highlight its value as a combinatorial target. SHIP2 inhibition represents a promising strategy to potentiate existing chemotherapies and targeted agents, opening new avenues for the treatment of refractory gastrointestinal cancers.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101130"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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The interplay between phosphoinositides and ESCRT proteins 磷酸肌苷与ESCRT蛋白之间的相互作用。

IF 2.4

Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2025-10-24 DOI: 10.1016/j.jbior.2025.101126

Chiara Giannini, Luca Ponzone, Nicola Barroero, Emilio Hirsch

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CD19 structure, expression, and signaling: From basic mechanisms to therapeutic targeting CD19结构、表达和信号传导：从基本机制到治疗靶向。

IF 2.4

Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2025-09-26 DOI: 10.1016/j.jbior.2025.101116

Stéphane Schurmans , Bastien Moës

{"title":"CD19 structure, expression, and signaling: From basic mechanisms to therapeutic targeting","authors":"Stéphane Schurmans , Bastien Moës","doi":"10.1016/j.jbior.2025.101116","DOIUrl":"10.1016/j.jbior.2025.101116","url":null,"abstract":"<div><div>CD19 is a central regulator of B-cell biology, acting both as a lineage marker and a critical modulator of signaling thresholds that govern development, activation, and tolerance. Structurally, CD19 is a heavily glycosylated transmembrane protein whose cytoplasmic domain harbors multiple tyrosine motifs serving as docking sites for key signaling molecules, including PI3K. Its expression is tightly regulated by transcriptional, post-transcriptional, and post-translational mechanisms, as well as by interactions with CD21 and CD81 in surface complexes. Genetic studies in mice and humans demonstrate that CD19 acts as a molecular rheostat, with both deficiency and overexpression leading to profound immunological dysfunctions ranging from hypogammaglobulinemia to autoimmunity. Importantly, recent work has revealed an additional level of CD19 signaling regulation mediated by conformational control of the CD19 cytoplasmic domain. A basic CD19 cytoplasmic juxtamembrane region engages in ionic interactions with PtdIns(4,5)P2, thereby influencing CD19 activation state. Loss of the 5-phosphatase INPP5K increases PtdIns(4,5)P2 levels, leading to constitutive CD19 signaling, impaired B-cell development and hypogammaglobulinemia. This discovery underscores the role of lipid–protein interactions in restraining inappropriate CD19 activation. Clinically, CD19 has emerged as a validated therapeutic target, with CAR T cells, bispecific antibodies, and monoclonal antibodies achieving remarkable efficacy in B-cell malignancies and autoimmune disorders. Understanding the fine regulation of CD19 expression, structure, and signaling remains essential to optimize therapeutic strategies.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101116"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Sixty-fifth international symposium on biological regulation and enzyme activity in normal and neoplastic tissues 第65届正常和肿瘤组织的生物调控和酶活性国际研讨会

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Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2026-01-29 DOI: 10.1016/j.jbior.2026.101148

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DGKζ depletion attenuates BRCA1-mediated DNA repair mechanism DGKζ缺失减弱了brca1介导的DNA修复机制。

IF 2.4

Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2025-10-21 DOI: 10.1016/j.jbior.2025.101118

Toshiaki Tanaka , Mitsuyoshi Iino , Kaoru Goto

{"title":"DGKζ depletion attenuates BRCA1-mediated DNA repair mechanism","authors":"Toshiaki Tanaka , Mitsuyoshi Iino , Kaoru Goto","doi":"10.1016/j.jbior.2025.101118","DOIUrl":"10.1016/j.jbior.2025.101118","url":null,"abstract":"<div><div>DNA double-strand breakage is the most lethal damage to chromosomal DNA. It activates a series of cellular DNA damage response pathways, including DNA damage sensing, control of cell cycle arrest and apoptosis, and DNA repair. DNA damage response pathways are regulated by complex signaling machineries. Of the intracellular signaling cascades, diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Because both DG and PA serve as second messengers, DGK activity induces a shift of signaling pathways from DG-mediated to PA-mediated cascades, thereby implicating DGK in the regulation of widely various functions. Reportedly, one member of the DGK family, DGKζ, is intimately involved in the regulation of stress responses through p53 and NF-κB. Stresses such as ischemia and infarction cause DGKζ downregulation. Experimental DGKζ depletion renders cells and mice vulnerable to various stressors such as chemotherapeutic agents and ionizing irradiation. Nevertheless, how DGKζ is involved in DNA repair, a critical event of DNA damage response for survival remains unknown. For this study, we examined how DGKζ depletion affects DNA repair mechanisms. We demonstrated that DGKζ depletion causes attenuation of Akt activation and DNA-PK protein expression upon DNA damage, which might engender downregulated BRCA1 protein synthesis and stability. Results suggest that DGKζ depletion attenuates BRCA1-mediated DNA repair machinery, thereby conferring vulnerability to DNA damage.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101118"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145375878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Group photo 合影

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Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2026-01-30 DOI: 10.1016/j.jbior.2026.101150

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OGT's inner circle: Protein interactions and functional impact OGT的核心：蛋白质相互作用和功能影响。

IF 2.4

Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2025-10-10 DOI: 10.1016/j.jbior.2025.101120

Fiddia Zahra , Natasha E. Zachara

{"title":"OGT's inner circle: Protein interactions and functional impact","authors":"Fiddia Zahra , Natasha E. Zachara","doi":"10.1016/j.jbior.2025.101120","DOIUrl":"10.1016/j.jbior.2025.101120","url":null,"abstract":"<div><div>The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as an essential post-translational modification in mammals. More than 5000 human proteins are subject to O-GlcNAcylation, influencing key cellular processes such as signal transduction, epigenetic regulation, transcription, translation, and bioenergetics. Dysregulation of this modification has been implicated in a wide range of diseases, including metabolic disorders, cancer, neurodegeneration, ischemic injury, and heart failure. O-GlcNAc-cycling is orchestrated by two enzymes: the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze the addition and removal of O-GlcNAc, respectively. A central challenge in the field is understanding how this minimal enzymatic machinery achieves such broad substrate specificity. It is hypothesized that OGT's functional versatility is mediated through interactions with a diverse network of protein partners that act as adaptors, scaffolds, or substrates, thereby directing its localization, modulating its activity, and shaping its substrate selectivity. In this review, we discuss key interactors and their functional impact on OGT. We also explore how post-translational modifications and substrate availability contribute to OGT regulation and specificity.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"99 ","pages":"Article 101120"},"PeriodicalIF":2.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Group photo 合影

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Advances in biological regulation Pub Date : 2026-01-01 Epub Date: 2026-01-30 DOI: 10.1016/j.jbior.2026.101149

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