Molecular Biology of the Cell最新文献

The DEAD-box RNA helicase DDX28 suppresses cell migration and 3D growth and invasion in MDA-MB-231 cells by altering bioenergetics. DEAD-box RNA解旋酶DDX28通过改变生物能量学抑制MDA-MB-231细胞的细胞迁移和3D生长和侵袭。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-25 DOI: 10.1091/mbc.E25-02-0052

Olivia Bebenek, Sydney A Pascetta, Joshua Steed, Morgan Mizzoni, Alexandria T Kellington, Margaret K Barnes, Tess Osorio-MacCready, James Uniacke

{"title":"The DEAD-box RNA helicase DDX28 suppresses cell migration and 3D growth and invasion in MDA-MB-231 cells by altering bioenergetics.","authors":"Olivia Bebenek, Sydney A Pascetta, Joshua Steed, Morgan Mizzoni, Alexandria T Kellington, Margaret K Barnes, Tess Osorio-MacCready, James Uniacke","doi":"10.1091/mbc.E25-02-0052","DOIUrl":"10.1091/mbc.E25-02-0052","url":null,"abstract":"Hypoxia is a common characteristic of the tumor microenvironment leading to aggressive phenotypes. A major response to hypoxia is through the induction of gene programs by the hypoxia-inducible factors (HIF). Previously, we showed that the DEAD-box RNA helicase DDX28 negatively regulates hypoxic eIF4E2-directed translation through its interaction with HIF-2α. We hypothesized that DDX28 is a tumor suppressor that represses the oncogenic HIF-2α axis. Here, we overexpress DDX28 in MDA-MB-231 breast cancer and U87MG glioblastoma cells that have very low and normal endogenous levels of DDX28, respectively, compared with noncancerous HEK293. We show that DDX28 suppresses cell migration, spheroid growth, and invasion in MDA-MB-231, but not U87MG cells. However, suppression is not through the HIF-2α gene program, but through DDX28 impacting cellular bioenergetics. DDX28 levels altered how cells utilized mitochondrial respiration and glycolysis for ATP generation. Furthermore, the pharmacological inhibition of these processes specifically reversed the effects of DDX28 overexpression. This study shows that low endogenous DDX28 levels promote hypoxic migration, and growth/invasion in three-dimensional structures in cells that have a bioenergetic profile that favors glycolysis such as MDA-MB-231.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar103"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Dysregulation of extracellular fibronectin and α5-integrin in dermal aging. 细胞外纤维连接蛋白和5-整合素在皮肤衰老中的失调。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-25 DOI: 10.1091/mbc.E25-02-0074

Yaelim Lee, Xingyu Shen, Oliver Dreesen, Jin Zhu, Rong Li

{"title":"Dysregulation of extracellular fibronectin and α5-integrin in dermal aging.","authors":"Yaelim Lee, Xingyu Shen, Oliver Dreesen, Jin Zhu, Rong Li","doi":"10.1091/mbc.E25-02-0074","DOIUrl":"10.1091/mbc.E25-02-0074","url":null,"abstract":"Dermal aging is a complex process characterized by structural and functional changes in the extracellular matrix (ECM) and the resident cells, such as dermal fibroblasts. Fibronectin (FN) ECM is a crucial component of the dermis, yet its role in natural aging remains poorly understood. Here, we demonstrate a significant reduction in FN ECM in aged, otherwise healthy, mouse dermis. To explore whether aging dermal fibroblasts contribute to this decline in FN levels, we examined human dermal fibroblasts (HDF) from aged skin and observed that they produce lower extracellular FN densities in vitro than young HDFs. This age-associated deficiency correlates with reduced level of α5-integrin, a cell-surface FN receptor essential for extracellular FN assembly. Knockdown of α5-integrin (α5KD) in young HDFs impairs FN ECM formation and induces phenotypes characteristic of cellular senescence. Interestingly, the proliferation defect in α5KD fibroblasts is largely restored by cell-derived matrices (CDMs) in vitro, highlighting the importance of ECM organization. These findings underscore the essential role of α5-integrin in maintaining proper ECM formation, which in turn protects against fibroblast senescence during dermal aging.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar99"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Reduced cell-substrate adhesion formation promotes cell migration in Dictyostelium. 减少细胞-底物黏附形成促进盘基骨鞘细胞迁移。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-11 DOI: 10.1091/mbc.E25-05-0230

Julio C Fierro Morales, Thu A Nguyen, Sabin Nepal, Chandler Redfearn, Bruce K Gale, Margaret A Titus, Minna Roh-Johnson

{"title":"Reduced cell-substrate adhesion formation promotes cell migration in Dictyostelium.","authors":"Julio C Fierro Morales, Thu A Nguyen, Sabin Nepal, Chandler Redfearn, Bruce K Gale, Margaret A Titus, Minna Roh-Johnson","doi":"10.1091/mbc.E25-05-0230","DOIUrl":"10.1091/mbc.E25-05-0230","url":null,"abstract":"Many cells adhere to the extracellular matrix (ECM) for efficient cell migration. This adhesion is mediated by focal adhesions, a protein complex linking the ECM to the intracellular cytoskeleton. Focal adhesions have been studied extensively in metazoan mesenchymal cells, but recent research in physiological contexts and amoeboid cells suggests that focal adhesion regulation differs from the mesenchymal focal adhesion paradigm. Although focal adhesion machinery predates the origin of metazoans, focal adhesion formation and regulation during nonmetazoan cell migration is largely unexplored. We used Dictyostelium discoideum to investigate potential novel mechanisms and the evolution of focal adhesion regulation, as Dictyostelium are nonmetazoans that form cell-substrate adhesion structures for migration. We show that PaxillinB, the Dictyostelium homologue of Paxillin, localizes to dynamic cell-substrate adhesions. As expected, PaxillinB mutations decreased the number of cell-substrate adhesions. Unexpectedly, however, decreased cell-substrate adhesion number led to an increase in cell migration speed. These findings are in direct contrast to Paxillin function at focal adhesions and regulation of cell migration in mammalian cells, challenging the established focal adhesion model and providing insight into the evolution of cell-substrate adhesions and Paxillin function during cell migration.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar98"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Mechanisms of growth-dependent regulation of the Gin4 kinase. 生长依赖性调节Gin4激酶的机制。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-04 DOI: 10.1091/mbc.E24-12-0568

Francisco Mendez Diaz, David Sanchez -Godinez, Francisco Solano, Akshi Jasani, Maria Alcaide-Gavilan, Beth E Prichard, Douglas R Kellogg

{"title":"Mechanisms of growth-dependent regulation of the Gin4 kinase.","authors":"Francisco Mendez Diaz, David Sanchez -Godinez, Francisco Solano, Akshi Jasani, Maria Alcaide-Gavilan, Beth E Prichard, Douglas R Kellogg","doi":"10.1091/mbc.E24-12-0568","DOIUrl":"10.1091/mbc.E24-12-0568","url":null,"abstract":"Cell-cycle progression is dependent upon cell growth. Cells must therefore translate growth into a proportional signal that indicates when there has been sufficient growth for cell-cycle progression. In budding yeast, the protein kinase Gin4 is required for normal control of bud growth and undergoes gradual multisite hyperphosphorylation and activation that are dependent upon bud growth and correlated with the extent of growth. Together, these observations suggest that Gin4 functions in mechanisms that measure cell growth. Here, we searched for signals that link Gin4 hyperphosphorylation to cell growth. We found that Elm1, a yeast homologue of mammalian Lkb1 kinases, is sufficient in vitro to induce full hyperphosphorylation of Gin4, and likely works by stimulating extensive autophosphorylation of Gin4. We further discovered that casein kinase Iγ, encoded by the YCK1 and YCK2 genes, is required for growth-dependent phosphorylation of Gin4. Yck1/2 are delivered to the growing plasma membrane by post-Golgi vesicles that drive membrane growth, and they are required for normal control of growth. The data suggest that delivery of Yck1/2 to the plasma membrane could play an important role in generating a growth-dependent signal that provides a measure of bud growth.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar94"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Nonmuscle myosin 2 without an assembly competence domain can incorporate into established filaments in cells. 没有装配能力结构域的非肌肉肌球蛋白2可以整合到细胞中已建立的细丝中。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-11 DOI: 10.1091/mbc.E24-07-0287

Kehan Wu, Hiral Patel, Huini Wu, Sasha K Demeulenaere, Vraj Patel, Margaret Utgaard, Melissa A Quintanilla, Margaret A Bennett, Stefano Sala, Jordan R Beach

{"title":"Nonmuscle myosin 2 without an assembly competence domain can incorporate into established filaments in cells.","authors":"Kehan Wu, Hiral Patel, Huini Wu, Sasha K Demeulenaere, Vraj Patel, Margaret Utgaard, Melissa A Quintanilla, Margaret A Bennett, Stefano Sala, Jordan R Beach","doi":"10.1091/mbc.E24-07-0287","DOIUrl":"10.1091/mbc.E24-07-0287","url":null,"abstract":"Myosin 2 dynamically assembles into filaments that exert force on the actin cytoskeleton. To form filaments, myosin 2 monomers transition between folded and unfolded states. Monomer unfolding exposes an extended coiled-coil that interacts with other monomers in parallel and antiparallel fashions, enabling bipolar filament formation. A C-terminal domain of the coiled-coil, termed assembly competence domain (ACD), has been repeatedly identified as necessary for filament assembly. Here, we revisit ACD contribution when full-length filaments are present. Nonmuscle myosin 2A lacking the ACD (∆ACD) initially appears diffuse, but triton extraction of cytosolic fraction reveals cytoskeletal association. Disruption of the folded monomer enhances the cytoskeletal fraction, while inhibition of endogenous filament assembly appears to reduce it. Finally, high-resolution imaging of endogenous and exogenous myosin 2 reveals highly coincident filamentous structures, suggesting that ∆ACD constructs coassemble with endogenous myosin 2A filaments. Our data demonstrate that while the ACD is required for de novo filament assembly, it is not required for monomers to recognize and associate with established filaments in cells. More broadly, this highlights the existence of distinct pathways governing how monomers participate in nascent filament assembly and how monomers recognize and associate with established filaments to maintain steady-state contractile networks.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar95"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Giardia's domed ventral disc architecture is essential for attachment and contributes to epithelial barrier disruption. 贾第鞭毛虫的弓形腹侧椎间盘结构对附着和上皮屏障破坏至关重要。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-11 DOI: 10.1091/mbc.E23-12-0515

K D Hagen, C Nosala, A Müller, N A Hilton, D Holthaus, J D Schulzke, S M Krug, T Hoffmann, M Laue, C Klotz, A Aebischer, S C Dawson

{"title":"Giardia's domed ventral disc architecture is essential for attachment and contributes to epithelial barrier disruption.","authors":"K D Hagen, C Nosala, A Müller, N A Hilton, D Holthaus, J D Schulzke, S M Krug, T Hoffmann, M Laue, C Klotz, A Aebischer, S C Dawson","doi":"10.1091/mbc.E23-12-0515","DOIUrl":"10.1091/mbc.E23-12-0515","url":null,"abstract":"Giardia lamblia is a widespread anaerobic protistan parasite causing significant diarrheal disease worldwide. Giardia trophozoites attach extracellularly to the host gastrointestinal epithelium using a unique microtubule (MT) organelle, the ventral disk. The complex, dome-shaped disk is composed of microribbon-cross-bridge (MR-CB) protein complexes scaffolded onto a spiral MT array. Attachment is dynamic and reversible, facilitating parasite contact and colonization of the gastrointestinal epithelium. To investigate possible contributions of disk-mediated attachment to host pathobiology, we generated a stable quadruple allelic knockout (KO) of an abundant disk-associated protein, MBP, using a new method of CRISPR-mediated gene disruption. MBPKO mutants had flattened crescent- or horseshoe-shaped discs, severe MR-CB defects, and complete phenotypic penetrance off selection. MBP mutants also had aberrant surface contacts and were unable to resist shear forces under fluid flow. Using a human gastrointestinal organoid model, we discovered that MBPKO mutants had a significantly reduced ability to cause the host epithelial barrier breakdown characteristic of wild-type infections. In contrast, the addition of spent medium or lysed parasites had no impact on epithelial barrier breakdown. Overall, this pioneering work provides direct evidence that MBP is required for the domed-disk architecture and that disk-mediated attachment contributes to host pathobiology, specifically epithelial barrier breakdown.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar93"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Cvm1 and its paralogue Cvm2 function as a complex at vacuolar membrane contact sites. Cvm1及其平行的Cvm2在液泡膜接触部位起复合体的作用。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-07-02 DOI: 10.1091/mbc.E25-02-0089

Daniel D Bisinski, Samira Klössel, René Rasche, Leonhard Breitsprecher, Nadine Gehle, Olympia Ekaterini Psathaki, Rodrigo Quiroga, Daniel Kümmel, Ayelén González Montoro

{"title":"Cvm1 and its paralogue Cvm2 function as a complex at vacuolar membrane contact sites.","authors":"Daniel D Bisinski, Samira Klössel, René Rasche, Leonhard Breitsprecher, Nadine Gehle, Olympia Ekaterini Psathaki, Rodrigo Quiroga, Daniel Kümmel, Ayelén González Montoro","doi":"10.1091/mbc.E25-02-0089","DOIUrl":"10.1091/mbc.E25-02-0089","url":null,"abstract":"Membrane contact sites are regions where organelle membranes come together, and serve as platforms for metabolite exchange, process organization, and regulation of organelle dynamics. The yeast vacuole, equivalent to lysosomes in higher eukaryotes, functions as a degradative organelle, storage compartment, and signaling hub, establishing contacts with multiple organelles. We previously identified the protein Cvm1 as a component of vacuole contact sites with mitochondria, the nuclear endoplasmic reticulum (ER), and peroxisomes. Here, we investigate Cvm1-mediated contacts and show that the contacts with mitochondria require the porins Por1 and Por2. Additionally, Cvm1 forms a protein complex with its paralogue Yml020w, which we designate as Cvm2. Bioinformatic analysis predicts that both proteins contain an α/β-hydrolase fold. Notably, the predicted catalytic triad of Cvm2 is essential for its in vivo function, while Cvm1 lacks an active site. Complex formation is necessary for the function of the proteins, and Cvm1 targets the complex to the vacuole by binding phosphatidylinositol-3-phosphate on this membrane. Overexpression of this complex generates extended contacts between the vacuole and the peripheral ER. Collectively, our work describes the novel Cvm1-Cvm2 complex and molecular interactions important for its function as part of vacuolar contact sites.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar104"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Domain-specific N-glycosylation of the adhesion G-protein-coupled receptor ADGRG6 N-terminal fragment regulates trafficking, proteolytic processing, and signaling. 粘附g蛋白偶联受体ADGRG6 n端片段的结构域特异性n-糖基化调节运输、蛋白水解加工和信号传导。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-07-02 DOI: 10.1091/mbc.E25-02-0060

Anandhu Jayachandran, Prabakaran Annadurai, Manas Upadhyay, Mansi Tiwari, Priyadatha Sajan, Prateek Sibal, Nayonika Chatterjee, Kasturi Pal

{"title":"Domain-specific N-glycosylation of the adhesion G-protein-coupled receptor ADGRG6 N-terminal fragment regulates trafficking, proteolytic processing, and signaling.","authors":"Anandhu Jayachandran, Prabakaran Annadurai, Manas Upadhyay, Mansi Tiwari, Priyadatha Sajan, Prateek Sibal, Nayonika Chatterjee, Kasturi Pal","doi":"10.1091/mbc.E25-02-0060","DOIUrl":"10.1091/mbc.E25-02-0060","url":null,"abstract":"Adhesion G-protein-coupled receptors (aGPCRs) are characterized by long extracellular N-terminus fragments (NTF) with several adhesive domains. Many aGPCRs are cleaved at the GPCR-autoproteolysis site (GPS), enclosed within the larger GPCR-autoproteolysis-inducing (GAIN) domain. Following cleavage at the endoplasmic reticulum (ER), the NTF and C-terminal fragments (CTF) heterodimerize, and the protomer is trafficked to the plasma membrane. ADGRG6 is an aGPCR playing important roles in embryonic development. It is activated by mechanical perturbation of the NTF and several extracellular matrix (ECM) proteins. GPCRs are known to undergo several posttranslational modifications (PTM) that regulate the molecular pharmacology of these receptors. N-glycosylation is an important PTM that regulates GPCR expression, trafficking, ligand binding, and signaling bias. Although ADGRG6 is N-glycosylated, the location of the glycans remains unknown. Furthermore, are there spatial roles of N-glycosylation in ADGRG6 processing, trafficking, and signaling? To address these gaps in knowledge, we used biochemical and cell-biological approaches using cell lines overexpressing wild-type and N-glycosylation mutants of ADGRG6. We demonstrate that specific N-glycan residues in different domains of the NTF of ADGRG6 have distinct roles in ADGRG6 autoproteolysis, furin cleavage, trafficking to the plasma membrane, and cAMP production.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar101"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Loss of negative regulation by HDAC1 and REST contributes to MAD1 overexpression in breast cancer. HDAC1和REST负调控缺失导致乳腺癌中MAD1过表达。

IF 3.1 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-04 DOI: 10.1091/mbc.E24-12-0582

Sarah E Copeland, Boya Chen, Avtar Roopra, Beth A Weaver

{"title":"Loss of negative regulation by HDAC1 and REST contributes to MAD1 overexpression in breast cancer.","authors":"Sarah E Copeland, Boya Chen, Avtar Roopra, Beth A Weaver","doi":"10.1091/mbc.E24-12-0582","DOIUrl":"10.1091/mbc.E24-12-0582","url":null,"abstract":"Mitotic arrest deficient 1 (MAD1), an essential component of the mitotic spindle assembly checkpoint, is commonly overexpressed in breast cancers where it serves as a marker of poor prognosis. MAD1 overexpression is sufficient to permit nontransformed cells to form orthotopic mammary tumors and to promote tumorigenesis in a recently described mouse model with inducible expression of endogenous Mad1. However, the mechanism of MAD1 up-regulation in cancer is unclear. Here, we report a 440-bp region of the MAD1L1 promoter that confers a repressive phenotype on MAD1L1 transcription. Bioinformatics analysis implicated histone deacetylase 1 (HDAC1) in MAD1L1 transcriptional regulation. Consistent with this, HDAC1 localizes to the MAD1L1 promoter and HDAC inhibition increases MAD1 mRNA and protein expression. The MAD1L1-repressive region contains a partial binding site for RE1-silencing transcription factor (REST), which utilizes HDAC1 as a cofactor. REST overexpression decreases MAD1 expression. Moreover, breast cancer patient samples show a significant negative correlation between REST and MAD1L1 mRNA expression. These results support a model in which an altered transcriptional program downstream of loss of the tumor-suppressor REST, which normally represses MAD1L1 transcription by recruiting HDAC1-containing repressive complexes, contributes to MAD1 overexpression in breast cancer.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"ar91"},"PeriodicalIF":3.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Sense, plug, and seal: proteins as both rapid responders and constitutive barriers supporting organelle compartmentalization. 感觉，堵塞和密封：蛋白质作为快速反应和构成屏障支持细胞器区隔化。

IF 2.7 3区生物学

Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-07-02 DOI: 10.1091/mbc.E23-08-0307

Megan C King, C Patrick Lusk, Nicholas R Ader

{"title":"Sense, plug, and seal: proteins as both rapid responders and constitutive barriers supporting organelle compartmentalization.","authors":"Megan C King, C Patrick Lusk, Nicholas R Ader","doi":"10.1091/mbc.E23-08-0307","DOIUrl":"10.1091/mbc.E23-08-0307","url":null,"abstract":"Although organellar compartmentalization is primarily established by the delimiting phospholipid bilayer membranes, the contribution of proteins has been less appreciated. Recently, studies across many realms of cell biology have put new focus on the role of proteins in acting as diffusion barriers in contexts where there are constitutive, regulated, or pathological discontinuities in membranes. Here, we synthesize longstanding observations of proteins acting as both barriers to lateral diffusion on membranes and diffusion in three-dimensional space. In particular, we focus on an emerging, conserved two-step paradigm of protein diffusion barriers that rapidly assemble in response to membranous organelle damage: a first phase of coincident sensing and stopgap \"plugging\" by responding repair proteins followed by a second phase of membrane sealing. We highlight recent work exemplifying this sense, plug, and seal paradigm at the postmitotic nuclear envelope and at ruptures of the interphase nuclear envelope, lysosomes, and the plasma membrane. Taken together, we highlight how cells use a variety of constitutive and induced proteinaceous barriers that support the role of biological membranes in defining organelle compartmentalization. Determining the biophysical nature of these barriers, and their means of \"sensing\" membrane rupture, will be an exciting avenue of future investigations.","PeriodicalId":18735,"journal":{"name":"Molecular Biology of the Cell","volume":" ","pages":"pe6"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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