Molecular and Cellular Biology最新文献_第2页

Key Mechanisms in Lysosome Stability, Degradation and Repair. 溶酶体稳定性、降解和修复的关键机制。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-09 DOI: 10.1080/10985549.2025.2494762

Rui Zhang, Marc A Vooijs, Tom Gh Keulers

{"title":"Key Mechanisms in Lysosome Stability, Degradation and Repair.","authors":"Rui Zhang, Marc A Vooijs, Tom Gh Keulers","doi":"10.1080/10985549.2025.2494762","DOIUrl":"10.1080/10985549.2025.2494762","url":null,"abstract":"Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"212-224"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018298","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

Erythropoietin Production in Embryonic Neural Cells is Controlled by Hypoxia Signaling and Histone Deacetylases with an Undifferentiated Cellular State. 胚胎神经细胞中促红细胞生成素的产生受缺氧信号和未分化细胞状态组蛋白去乙酰化酶的控制。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-12-02 DOI: 10.1080/10985549.2024.2428717

Yuma Iwamura, Taku Nakai, Koichiro Kato, Hirotaka Ishioka, Masayuki Yamamoto, Ikuo Hirano, Norio Suzuki

{"title":"Erythropoietin Production in Embryonic Neural Cells is Controlled by Hypoxia Signaling and Histone Deacetylases with an Undifferentiated Cellular State.","authors":"Yuma Iwamura, Taku Nakai, Koichiro Kato, Hirotaka Ishioka, Masayuki Yamamoto, Ikuo Hirano, Norio Suzuki","doi":"10.1080/10985549.2024.2428717","DOIUrl":"10.1080/10985549.2024.2428717","url":null,"abstract":"During mammalian development, production sites of the erythroid growth factor erythropoietin (EPO) shift from the neural tissues to the liver in embryos and to the kidneys in adults. Embryonic neural EPO-producing (NEP) cells, a subpopulation of neuroepithelial and neural crest cells, express the Epo gene between embryonic day (E) 8.5 and E11.5 to promote primitive erythropoiesis in mice. While Epo gene expression in the liver and kidneys is induced under hypoxic conditions through hypoxia-inducible transcription factors (HIFs), the Epo gene regulatory mechanisms in NEP cells remain to be elucidated. Here, we confirmed the presence of cells co-expressing EPO and HIFs in mouse neural tubes, where the hypoxic microenvironment activates HIFs. Chemical activation and inhibition of HIFs demonstrated the hypoxic regulation of EPO expression in human fetal neural progenitors and mouse embryonic neural tissues. In addition, we found that histone deacetylase inhibitors can reactivate EPO production in cell lines derived from NEP cells and human neuroblastoma, as well as in mouse primary neural crest cells, while rejuvenating these cells. Furthermore, the ability of the rejuvenated cells to produce EPO was maintained in hypoxia. Thus, EPO production is controlled by epigenetic mechanisms and hypoxia signaling in the immature state of hypoxic NEP cells.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"32-45"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142770614","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

ALYREF Promotes Progression of Intrahepatic Cholangiocarcinoma through Increasing the Level of Isocitrate Dehydrogenase 1 in an m5C-Dependent Manner. ALYREF通过以m5c依赖的方式增加异柠檬酸脱氢酶1的水平，促进肝内胆管癌的进展。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-14 DOI: 10.1080/10985549.2025.2490031

Zhiqiang Hao, Haixiang Yang, Wei Zhu, Dedong Yu, Yanjie Cao, Yun Wu

{"title":"ALYREF Promotes Progression of Intrahepatic Cholangiocarcinoma through Increasing the Level of Isocitrate Dehydrogenase 1 in an m5C-Dependent Manner.","authors":"Zhiqiang Hao, Haixiang Yang, Wei Zhu, Dedong Yu, Yanjie Cao, Yun Wu","doi":"10.1080/10985549.2025.2490031","DOIUrl":"https://doi.org/10.1080/10985549.2025.2490031","url":null,"abstract":"RNA 5-methylcytosine (m5C) modification has emerged as an important regulatory mechanism in the progression of human cancers, including hepatobiliary tumors. The m5C \"reader\" Aly/REF export factor (ALYREF) was recently found to be identified as a prognostic biomarker in liver cancer. However, its exact role in intrahepatic cholangiocarcinoma (ICC) progression is unclear. In this study, ALYREF was found to be upregulated in ICC tissues and cells. The gain- and loss-of-function experiments indicated that ALYREF promoted cell proliferation and invasion and suppressed cell apoptosis. Moreover, we found that isocitrate dehydrogenase 1 (IDH1), a metastatic marker of liver cancer, was also upregulated in ICC tissues, displayed a relatively strong positive correlation with the level of ALYREF, and was positively regulated by ALYREF. As an m5C \"reader\", ALYREF interacted with m5C-IDH1 mRNA and increased its stability. ALYREF knockdown partially eliminated the promotion of IDH1 on ICC cell proliferation and invasion. ALYREF positively regulated NRF2-driven glutathione synthesis in ICC cells, which was reversed by IDH1 silencing. Finally, in a xenograft tumor mouse model, knockdown of ALYREF or treatment with ivosidenib (an IDH1 inhibitor) significantly suppressed tumor growth in vivo. In conclusion, ALYREF promotes ICC progression by increasing IDH1 levels in an m5C-dependent manner.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"45 5","pages":"198-211"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079054","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

Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria. 了解胱氨酸-合成酶基因突变的影响：探索同型半胱氨酸尿的新疗法。

IF 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-06-10 DOI: 10.1080/10985549.2025.2511338

Tomas Majtan, Ela Mijatovic, Maria Petrosino

{"title":"Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria.","authors":"Tomas Majtan, Ela Mijatovic, Maria Petrosino","doi":"10.1080/10985549.2025.2511338","DOIUrl":"10.1080/10985549.2025.2511338","url":null,"abstract":"Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS regulates methionine conversion into metabolites critical for redox balance (cysteine, glutathione) and signaling (H2S). Pathogenic missense mutations in the CBS gene often impair folding, cofactor binding, stability or oligomerization rather than targeting the key catalytic residues of the CBS enzyme. Advances in understanding of CBS folding and assembly as well as CBS interactions with cellular proteostasis network offer potential for therapies using pharmacological chaperones (PCs), i.e., compounds facilitating proper folding, assembly or cellular trafficking. This review discusses progress in identifying PCs for HCU, including chemical chaperones, cofactors, and proteasome inhibitors. We outline future directions, focusing on high-throughput screening and structure-based drug design to develop CBS-specific PCs. These could stabilize mutant CBS, enhance its stability and restore activity, providing new treatments for HCU and possibly other conditions related to dysregulated CBS, such as cancer or Down's syndrome.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"327-342"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266709","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

Nuclear Roles for Canonically Lysosomal Proteases. 典型溶酶体蛋白酶的核作用。

IF 2.7 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-06-22 DOI: 10.1080/10985549.2025.2519158

Anna E Enneking, Marc M Khorey, Laura E Edgington-Mitchell

{"title":"Nuclear Roles for Canonically Lysosomal Proteases.","authors":"Anna E Enneking, Marc M Khorey, Laura E Edgington-Mitchell","doi":"10.1080/10985549.2025.2519158","DOIUrl":"10.1080/10985549.2025.2519158","url":null,"abstract":"While the cysteine proteases legumain and cathepsins have traditionally been known as \"lysosomal\" proteases, there is increasing evidence to suggest that they also contribute to a wide range of extralysosomal processes, including in the nucleus. This review aims to provide a comprehensive overview of the current knowledge regarding the translocation of these proteases to the nucleus and their functions on arrival. We discuss possible mechanisms for transporting these proteases to the nucleus, including the presence of a nuclear localization signal sequence or hitchhiking on other proteins that possess this sequence. This transport requires the proteases to first reach the cytosol, which may occur via direct cytosolic translation of truncated proteases or downstream of lysosomal membrane permeabilization. We also discuss the evidence for functions of these proteases upon arrival to the nucleus, including cell cycle progression, cell differentiation, cell death, immune regulation, and epigenetic regulation. As protease substrate profiling methods continue to improve, it is anticipated that many new nuclear substrates and interacting partners will be identified to reveal additional functions for nuclear proteases.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"343-352"},"PeriodicalIF":2.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144369067","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

Defining and Harnessing the Megakaryocyte/Platelet Checkpoint. 定义和利用巨核细胞/血小板检查点。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-02-24 DOI: 10.1080/10985549.2025.2451279

Alexandra Mazharian, Yotis A Senis

{"title":"Defining and Harnessing the Megakaryocyte/Platelet Checkpoint.","authors":"Alexandra Mazharian, Yotis A Senis","doi":"10.1080/10985549.2025.2451279","DOIUrl":"10.1080/10985549.2025.2451279","url":null,"abstract":"Platelets, or thrombocytes are anucleate cell fragments of megakaryocytes (MKs) that are highly reactive to sites of vascular injury and implicated in many pathologies. However, the molecular mechanisms regulating the number and activity of platelets in the circulation remain undefined. The primary outstanding question remains what is the triggering mechanism of platelet production, or thrombopoiesis? Putative stimulatory factors and mechanical forces are thought to drive this process, but none induce physiological levels of thrombopoiesis. Intrinsic inhibitory mechanisms that maintain MKs in a refractory state in sites of thrombopoiesis are conspicuously overlooked, as well as extrinsic cues that release this brake system, allowing asymmetric platelet production to proceed toward the vascular lumen. Here we introduce the novel concept of a MK/platelet checkpoint, putative components and a working model of how it may be regulated. We postulate that the co-inhibitory receptor G6b-B and the non-transmembrane protein-tyrosine phosphatases (PTPs) Shp1 and Shp2 form an inhibitory complex that is the primary gatekeeper of this checkpoint, which is spatiotemporally regulated by the receptor-type PTP CD148 and vascular heparan sulfate proteoglycans. By advancing this alternative model of thrombopoiesis, we hope to stimulate discourse and a shift in how we conceptualize and address this fundamental question.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"116-128"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483701","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

HEB Restrains Effector Gene Expression during Early CD8⁺ Memory Precursor T Cell Differentiation. HEB在早期CD8+记忆前体T细胞分化过程中抑制效应基因表达

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-05-26 DOI: 10.1080/10985549.2025.2505730

Joanne Pui-Ting Leung, Siamak Haddadi, Michael J Geuenich, Alara Tuncer, Vivien Musiime, Chao Wang, Juan-Carlos Zúñiga-Pflücker, Kieran R Campbell, Michele K Anderson

{"title":"HEB Restrains Effector Gene Expression during Early CD8+ Memory Precursor T Cell Differentiation.","authors":"Joanne Pui-Ting Leung, Siamak Haddadi, Michael J Geuenich, Alara Tuncer, Vivien Musiime, Chao Wang, Juan-Carlos Zúñiga-Pflücker, Kieran R Campbell, Michele K Anderson","doi":"10.1080/10985549.2025.2505730","DOIUrl":"10.1080/10985549.2025.2505730","url":null,"abstract":"Memory T cells are essential for maintaining long-term adaptive immunity. Memory cell precursors and short-lived effector cells emerge from undifferentiated naïve T cells directly downstream of TCR signaling but little is known about how this lineage choice is regulated at the molecular level. The transcription factor HEB is known to be an important regulator of thymic T cell development, but how it functions in peripheral T cell differentiation is poorly understood. We assessed the role of HEB in the differentiation of memory-like T cell precursors by inducing TCR signaling in CD8 T cells in the context of memory-polarizing cytokines or inflammatory conditions and found that CD8 T cells from HEB-deficient mice underwent accelerated differentiation as compared to WT cells. Transcriptomic analysis revealed aberrant upregulation of immune response genes and decreased expression of genes promoting stemness from the earliest stages of post-TCR signal activation and persisting throughout the course of differentiation. In addition, acute viral infection of HEB cKO mice resulted in enhanced memory precursor cell formation and increased effector functionality. Therefore, we have identified HEB as a central participant in the gene regulatory networks that regulate early CD8 memory T cell differentiation and effector gene expression. This study showed that naïve CD8 T cells lacking HEB exhibit increased TCR signal strength and loss of signatures of stem-ness, revealing a role for HEB in promoting immune memory.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"283-300"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142911","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

Impact of Short-Term Lipid Overload on Whole-Body Physiology. 短期脂质超载对全身生理的影响。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2024-12-27 DOI: 10.1080/10985549.2024.2438814

Umur Keles, Nisan Ece Kalem-Yapar, Hanna Hultén, Li Na Zhao, Philipp Kaldis

{"title":"Impact of Short-Term Lipid Overload on Whole-Body Physiology.","authors":"Umur Keles, Nisan Ece Kalem-Yapar, Hanna Hultén, Li Na Zhao, Philipp Kaldis","doi":"10.1080/10985549.2024.2438814","DOIUrl":"10.1080/10985549.2024.2438814","url":null,"abstract":"Complex metabolic diseases due to overnutrition such as obesity, type 2 diabetes, and fatty liver disease are a major burden on the healthcare system worldwide. Current research primarily focuses on disease endpoints and trying to understand underlying mechanisms at relatively late stages of the diseases, when irreversible damage is already done. However, complex interactions between physiological systems during disease development create a problem regarding how to build cause-and-effect relationships. Therefore, it is essential to understand the early pathophysiological effects of overnutrition, which can help us understand the origin of the disease and to design better treatment strategies. Here, we focus on early metabolic events in response to high-fat diets (HFD) in rodents. Interestingly, insulin resistance, fatty liver, and obesity-promoting systemic inflammatory responses are evident within a week when mice are given consecutive HFD meals. However, as shown in human studies, these effects are usually not visible after a single meal. Overall, these results suggest that sustained HFD-intake within days can create a hyperlipidemic environment, globally remodeling metabolism in all affected organs and resembling some of the important disease features.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"47-58"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896060","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

Investigating the Aggregation and Prionogenic Properties of Human Cancer-Related Proteins. 研究人类癌症相关蛋白的聚集和致朊特性。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-03-31 DOI: 10.1080/10985549.2025.2481054

Dustin Goncharoff, Zhiqiang Du, Shriram Venkatesan, Brandon Cho, Jenny Zhao, Milad J Alasady, Dalton Huey, Hannah Ma, Jake Rosenthal, Alexander Turenitsa, Coral Feldman, Randal Halfmann, Marc L Mendillo, Liming Li

{"title":"Investigating the Aggregation and Prionogenic Properties of Human Cancer-Related Proteins.","authors":"Dustin Goncharoff, Zhiqiang Du, Shriram Venkatesan, Brandon Cho, Jenny Zhao, Milad J Alasady, Dalton Huey, Hannah Ma, Jake Rosenthal, Alexander Turenitsa, Coral Feldman, Randal Halfmann, Marc L Mendillo, Liming Li","doi":"10.1080/10985549.2025.2481054","DOIUrl":"10.1080/10985549.2025.2481054","url":null,"abstract":"Cancer encompasses a range of severe diseases characterized by uncontrolled cell growth and the potential for metastasis. Understanding the mechanism underlying tumorigenesis has been a central focus of cancer research. Self-propagating protein aggregates, known as prions, are linked to various biological functions and diseases, particularly those related to mammalian neurodegeneration. However, it remains unclear whether prion-like mechanisms contribute to tumorigenesis and cancer. Using a combined approach of algorithmic predictions, alongside genetic and biochemical experimentation, we identified numerous cancer-associated proteins prone to aggregation, many of which contain prion-like domains (PrLDs). These predictions were experimentally validated for both aggregation and prion-formation. We demonstrate that several PrLDs undergo nucleation-limited amyloid formation, which can alter protein activity in a mitotically heritable fashion. These include SSXT, a subunit of the chromatin-remodeling BAF (hSWI/SNF) complexes; CLOCK, a core component of the circadian clock; and EPN4, a clathrin-interacting protein involved in protein trafficking between the trans-Golgi network and endosomes. The prions formed by these PrLDs occurred in multiple variants and depended on Hsp104, a molecular chaperone with disaggregase activity. Our results reveal an inherent tendency for prion-like aggregation in human cancer-associated proteins, suggesting a potential role for such aggregation in the epigenetic changes driving tumorigenesis.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"154-168"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753558","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

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