Molecular and Cellular Biology最新文献_第2页

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

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

Loss of HNRNPK During Cell Senescence Linked to Reduced Production of CDC20. 细胞衰老过程中HNRNPK的丢失与CDC20的产生减少有关。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-01-13 DOI: 10.1080/10985549.2024.2443590

Chang Hoon Shin, Martina Rossi, Krystyna Mazan-Mamczarz, Jennifer L Martindale, Rachel Munk, Apala Pal, Yulan Piao, Jinshui Fan, Supriyo De, Kotb Abdelmohsen, Myriam Gorospe

{"title":"Loss of HNRNPK During Cell Senescence Linked to Reduced Production of CDC20.","authors":"Chang Hoon Shin, Martina Rossi, Krystyna Mazan-Mamczarz, Jennifer L Martindale, Rachel Munk, Apala Pal, Yulan Piao, Jinshui Fan, Supriyo De, Kotb Abdelmohsen, Myriam Gorospe","doi":"10.1080/10985549.2024.2443590","DOIUrl":"10.1080/10985549.2024.2443590","url":null,"abstract":"Cellular senescence is a complex biological response to sublethal damage. The RNA-binding protein HNRNPK was previously found to decrease prominently during senescence in human diploid fibroblasts. Here, analysis of the mechanisms leading to reduced HNRNPK abundance revealed that in cells undergoing senescence, HNRNPK mRNA levels declined transcriptionally and full-length HNRNPK protein was progressively lost, while the abundance of a truncated HNRNPK increased. The ensuing loss of full-length HNRNPK enhanced cell cycle arrest along with increased DNA damage. Analysis of the RNAs enriched after HNRNPK ribonucleoprotein immunoprecipitation (RIP) revealed a prominent target of HNRNPK, CDC20 mRNA, encoding a protein critical for progression through the G2/M phase of the cell division cycle. Silencing HNRNPK markedly decreased the levels of CDC20 mRNA via reduced transcription and stability of CDC20 mRNA, leading to lower CDC20 protein levels; conversely, overexpressing HNRNPK increased CDC20 production. Depletion of either HNRNPK or CDC20 impaired cell proliferation, with a concomitant reduction in the levels of CDK1, a key kinase for progression through G2/M. Given that overexpressing CDC20 in HNRNPK-silenced cells partly alleviated growth arrest, we propose that the reduction in HNRNPK levels in senescent cells contributed to inhibiting proliferation at least in part by suppressing CDC20 production.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"129-141"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971510","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

Noncoding RNA, ncRNA-a3, Epigenetically Regulates TAL1 Transcriptional Program During Erythropoiesis. 非编码RNA， ncRNA-a3，在红细胞生成过程中表观遗传调控TAL1转录程序。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2025-01-01 Epub Date: 2025-04-10 DOI: 10.1080/10985549.2025.2482079

Meghana Matur, Yasin Uzun, Xiangguo Shi, Karina Hamamoto, Yi Qiu, Suming Huang

{"title":"Noncoding RNA, ncRNA-a3, Epigenetically Regulates TAL1 Transcriptional Program During Erythropoiesis.","authors":"Meghana Matur, Yasin Uzun, Xiangguo Shi, Karina Hamamoto, Yi Qiu, Suming Huang","doi":"10.1080/10985549.2025.2482079","DOIUrl":"https://doi.org/10.1080/10985549.2025.2482079","url":null,"abstract":"Hematopoietic transcription is a combinatorial control of transcription factors, chromatin modifiers, and non-coding RNAs. TAL1 is a critical regulator of normal and malignant hematopoiesis. However, mechanism underlying regulation of TAL1 activity during erythropoiesis versus leukemogenesis remains elusive. Here, we showed that an enhancer RNA, ncRNA-a3 transcribed from TAL1 + 51Kb-enhancer, is positively correlated with TAL1 locus chromatin accessibility and transcription, and required for TAL1 activation during EPO-induced erythropoiesis. Loss of ncRNA-a3 in CD34+ hematopoietic stem and progenitor cells leads to reduction of TAL1 transcription, followed by impaired terminal erythroid differentiation. The effect of ncRNA-a3 loss on erythroid differentiation is partially rescued by overexpression of Tal1 cDNA, suggesting an important role of ncRNA-a3/TAL1 regulatory axis in erythropoiesis. Mechanistically, ncRNA-a3 regulates long-range chromatin interactions between +51Kb erythroid-specific enhancer, promoter and other regulatory elements in the TAL1 locus to maintain the erythroid interaction hub. By facilitating the binding and recruitment of p300/BRG1 to the TAL1 locus, ncRNA-a3 promotes chromatin accessibility in the TAL1 locus and activates TAL1 transcription program, including subsequent epigenetic and transcriptional activation of erythroid-specific TAL1 target genes. Our study reveals a novel role for ncRNA-a3 in TAL1 dependent erythropoiesis and establishes a new mode of ncRNA-a3 action in TAL1 transcriptional activation.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"45 4","pages":"169-184"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The 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 3.2 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":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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