Molecular and Cellular Biology最新文献

{"title":"Mitochondrial Fragmentation Promotes Inflammation Resolution Responses in Macrophages via Histone Lactylation.","authors":"Leah I Susser, My-Anh Nguyen, Michele Geoffrion, Christina Emerton, Mireille Ouimet, Mireille Khacho, Katey J Rayner","doi":"10.1080/10985549.2023.2253131","DOIUrl":"10.1080/10985549.2023.2253131","url":null,"abstract":"<p><p>During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated \"M1\", or pro-resolving/alternatively \"M2\" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"531-546"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d5/8a/TMCB_43_2253131.PMC10569354.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135311","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}

{"title":"A SNAI2/CTCF Interaction is Required for <i>NOTCH1</i> Expression in Rhabdomyosarcoma.","authors":"Prethish Sreenivas, Long Wang, Meng Wang, Anil Challa, Paulomi Modi, Nicole Rae Hensch, Berkley Gryder, Hsien-Chao Chou, Xiang R Zhao, Benjamin Sunkel, Rodrigo Moreno-Campos, Javed Khan, Benjamin Z Stanton, Myron S Ignatius","doi":"10.1080/10985549.2023.2256640","DOIUrl":"10.1080/10985549.2023.2256640","url":null,"abstract":"<p><p>Rhabdomyosarcoma (RMS) is a pediatric malignancy of the muscle with characteristics of cells blocked in differentiation. <i>NOTCH1</i> is an oncogene that promotes self-renewal and blocks differentiation in the fusion negative-RMS sub-type. However, how <i>NOTCH1</i> expression is transcriptionally maintained in tumors is unknown. Analyses of SNAI2 and CTCF chromatin binding and HiC analyses revealed a conserved SNAI2/CTCF overlapping peak downstream of the <i>NOTCH1</i> locus marking a sub-topologically associating domain (TAD) boundary. Deletion of the SNAI2-CTCF peak showed that it is essential for <i>NOTCH1</i> expression and viability of FN-RMS cells. Reintroducing constitutively activated <i>NOTCH1</i>-ΔE in cells with the SNAI2-CTCF peak deleted restored cell-viability. Ablation of SNAI2 using CRISPR/Cas9 reagents resulted in the loss of majority of RD and SMS-CTR FN-RMS cells. However, the few surviving clones that repopulate cultures have recovered <i>NOTCH1</i>. Cells that re-establish <i>NOTCH1</i> expression after SNAI2 ablation are unable to differentiate robustly as SNAI2 shRNA knockdown cells; yet, <i>SNAI2</i>-ablated cells continued to be exquisitely sensitive to ionizing radiation. Thus, we have uncovered a novel mechanism by which SNAI2 and CTCF maintenance of a sub-TAD boundary promotes rather than represses <i>NOTCH1</i> expression. Further, we demonstrate that SNAI2 suppression of apoptosis post-radiation is independent of <i>SNAI2</i>/<i>NOTCH1</i> effects on self-renewal and differentiation.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"547-565"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50162157","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}

{"title":"Module 4-Deficient CCN2/Connective Tissue Growth Factor Attenuates the Progression of Renal Fibrosis via Suppression of Focal Adhesion Kinase Phosphorylation in Tubular Epithelial Cells.","authors":"Hiroaki Amano, Tsutomu Inoue, Takeru Kusano, Daichi Fukaya, Wakako Kosakai, Hirokazu Okada","doi":"10.1080/10985549.2023.2253130","DOIUrl":"10.1080/10985549.2023.2253130","url":null,"abstract":"<p><p>CCN2/connective tissue growth factor (CTGF) potentially serves as a therapeutic target for chronic kidney disease. Here we investigated CCN2 module-4, encoded by <i>Ccn2</i> exon 5, through the generation of <i>Ccn2</i> exon 5 knockout mice (<i>Ex5^-/-</i> mice). To investigate renal fibrosis pathogenesis, <i>Ex5^-/-</i> mice were employed to model unilateral ureteral obstruction (UUO), unilateral ischemic-reperfusion injury (UIRI), and 5/6 nephrectomy. Interstitial fibrosis was significantly attenuated in the <i>Ex5^-/-</i> mice in the three models. Furthermore, phosphorylated focal adhesion kinase (FAK) levels in tubular epithelial cells were significantly lower in the kidneys of the UUO- and UIRI-<i>Ex5^-/-</i> mice than those of the <i>Ex5^+/+</i> mice. Moreover, CCN2 module 4-mediated renal tubule FAK and promoted fibrosis. These findings indicate that CCN2 module-4-FAK pathway components will serve as therapeutic targets for effectively attenuating renal fibrosis.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"515-530"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41163630","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}

{"title":"Hypoxia-Inducible Factor-2alpha Affects the MEK/ERK Signaling Pathway via Primary Cilia in Connection with the Intraflagellar Transport Protein 88 Homolog.","authors":"Tristan Leu, Jannik Denda, Anna Wrobeln, Joachim Fandrey","doi":"10.1080/10985549.2023.2198931","DOIUrl":"10.1080/10985549.2023.2198931","url":null,"abstract":"<p><p>The ability of cells to communicate with their surrounding is a prerequisite for essential processes such as proliferation, apoptosis, migration, and differentiation. To this purpose, primary cilia serve as antennae-like structures on the surface of most mammalian cell types. Cilia allow signaling via hedgehog, Wnt or TGF-beta pathways. Their length, in part controlled by the activity of intraflagellar transport (IFT), is a parameter for adequate function of primary cilia. Here we show, in murine neuronal cells, that intraflagellar transport protein 88 homolog (IFT88) directly interacts with the hypoxia-inducible factor-2α (HIF-2α), hitherto known as an oxygen-regulated transcription factor. Furthermore, HIF-2α accumulates in the ciliary axoneme and promotes ciliary elongation under hypoxia. Loss of HIF-2α affected ciliary signaling in neuronal cells by decreasing transcription of <i>Mek1/2</i> and <i>Erk1/2</i>. Targets of the MEK/ERK signaling pathway, such as <i>Fos</i> and <i>Jun</i>, were significantly decreased. Our results suggest that HIF-2α influences ciliary signaling by interacting with IFT88 under hypoxic conditions. This implies an unexpected and far more extensive function of HIF-2α than described before.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 4","pages":"174-183"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9458670","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}

{"title":"The \"LINC\" between Δ40p53-miRNA Axis in the Regulation of Cellular Homeostasis.","authors":"Apala Pal, Pritam Kumar Ghosh, Saumitra Das","doi":"10.1080/10985549.2023.2213147","DOIUrl":"10.1080/10985549.2023.2213147","url":null,"abstract":"<p><p>Previous research has shown that Δ40p53, the translational isoform of p53, can inhibit cell growth independently of p53 by regulating microRNAs. Here, we explored the role of Δ40p53 in regulating the long noncoding RNA-micro-RNA-cellular process axis, specifically focusing on <i>LINC00176</i>. Interestingly, <i>LINC00176</i> levels were predominantly affected by the overexpression/stress-mediated induction and knockdown of Δ40p53 rather than p53 levels. Additional assays revealed that Δ40p53 transactivates <i>LINC00176</i> transcriptionally and could also regulate its stability. RNA immunoprecipitation experiments revealed that <i>LINC00176</i> sequesters several putative microRNA targets, which could further titrate several mRNA targets involved in different cellular processes. To understand the downstream effects of this regulation, we ectopically overexpressed and knocked down <i>LINC00176</i> in HCT116 p53-/- (harboring only Δ40p53) cells, which affected their proliferation, cell viability, and expression of epithelial markers. Our results provide essential insights into the pivotal role of Δ40p53 in regulating the novel <i>LINC00176</i> RNA-microRNA-mRNA axis independent of FL-p53 and in maintaining cellular homeostasis.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 7","pages":"335-353"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9796862","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}

{"title":"Correction.","authors":"","doi":"10.1080/10985549.2023.2245732","DOIUrl":"10.1080/10985549.2023.2245732","url":null,"abstract":"In several of the figure panels in this publication (Figs 1A, 2C, 3A), intervening lanes were spliced out to remove data not important for our conclusions and this was not indicated in the published figures. In another figure (Fig 5A), concerns were raised on PUBPEER about whether this image contained unannotated lane splicing and alteration of the image background (https://pubpeer.com/publications/765E62F7376C08 BCC55EF73CF232DA). We examined the original data (Western Blot images from the Odyssey imaging system and transcription assay results from phosphorimager data) and made revised figure panels using current accepted standards for figure preparation. There are no changes in any of the conclusions from these corrections and the revised figures look essentially the same as the published figures except that the lane splices are clearly indicated. Examination of the data used to generate Fig 5A showed no lane splicing or alteration of the image background and a high-resolution image of the original data was used to make a revised figure. All original data (uncropped gel images and revised figures) are publicly available at Mendeley data (https://data.mendeley.com/datasets/kkx4tyjyg7/1).","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 9","pages":"481-483"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512925/pdf/TMCB_43_2245732.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10307205","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}

{"title":"Claspin is Required for Growth Recovery from Serum Starvation through Regulating the PI3K-PDK1-mTOR Pathway in Mammalian Cells.","authors":"Chi-Chun Yang,&nbsp;Hisao Masai","doi":"10.1080/10985549.2022.2160598","DOIUrl":"https://doi.org/10.1080/10985549.2022.2160598","url":null,"abstract":"<p><p>Claspin plays multiple important roles in regulation of DNA replication as a mediator for the cellular response to replication stress, an integral replication fork factor that facilitates replication fork progression and a factor that promotes initiation by recruiting Cdc7 kinase. Here, we report a novel role of Claspin in growth recovery from serum starvation, which requires the activation of PI3 kinase (PI3K)-PDK1-Akt-mTOR pathways. In the absence of Claspin, cells do not proceed into S phase and eventually die partially in a ROS- and p53-dependent manner. Claspin directly interacts with PI3K and mTOR, and is required for activation of PI3K-PDK1-mTOR and for that of mTOR downstream factors, p70S6K and 4EBP1, but not for p38 MAPK cascade during the recovery from serum starvation. PDK1 physically interacts with Claspin, notably with CKBD, in a manner dependent on phosphorylation of the latter protein, and is required for interaction of mTOR with Claspin. Thus, Claspin plays a novel role as a key regulator for nutrition-induced proliferation/survival signaling by activating the mTOR pathway. The results also suggest a possibility that Claspin may serve as a common mediator that receives signals from different PI3K-related kinases and transmit them to specific downstream kinases.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 1","pages":"1-21"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ff/64/TMCB_43_2160598.PMC9936878.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9120081","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}

{"title":"Transcriptional Regulation of <i>Math1</i> by Aryl Hydrocarbon Receptor: Effect on Math1⁺ Progenitor Cells in Mouse Small Intestine.","authors":"Yoko Yagishita, Tanvi Joshi, Thomas W Kensler, Nobunao Wakabayashi","doi":"10.1080/10985549.2022.2160610","DOIUrl":"10.1080/10985549.2022.2160610","url":null,"abstract":"<p><p>The physiological roles of aryl hydrocarbon receptor (AhR) in the small intestine have been revealed as immunomodulatory and barrier functions. However, its contributions to cell fate regulation are incompletely understood. The Notch-activated signaling cascade is a central component of intestinal cell fate determinations. The lateral inhibitory mechanism governed by Notch directs cell fates toward distinct cell lineages (i.e., absorptive and secretory cell lineages) through its downstream effector, mouse atonal homolog 1 (MATH1). An investigation employing cell lines and intestinal crypt cells revealed that AhR regulates <i>Math1</i> expression in a xenobiotic response element (XRE)-dependent manner. The AhR-<i>Math1</i> axis was further addressed using intestinal organoids, where AhR-<i>Math1</i> and HES1-<i>Math1</i> axes appeared to coexist within the underlying <i>Math1</i> transcriptional machinery. When the HES1-<i>Math1</i> axis was pharmacologically suppressed, β-naphthoflavone-mediated AhR activation increased the number of goblet and Math1⁺ progenitor cells in the organoids. The same pharmacological dissection of the AhR-<i>Math1</i> axis was applied in vivo, demonstrating an enhanced number of Math1⁺ progenitor cells in the small intestine following AhR activation. We report here that AhR-<i>Math1</i> is a direct transcriptional axis with effects on Math1⁺ progenitor cells in the small intestine, highlighting a novel molecular basis for fine-tuning Notch-mediated cell fate regulation.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 1","pages":"43-63"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9937019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9120082","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}

{"title":"A CDK-Dependent Phosphorylation of a Novel Domain of Rif1 Regulates its Function during Telomere Damage and Other Types of Stress.","authors":"Cameron M Robertson,&nbsp;Yuan Xue,&nbsp;Shobir Chowdhury,&nbsp;Laura Maringele","doi":"10.1080/10985549.2023.2193768","DOIUrl":"https://doi.org/10.1080/10985549.2023.2193768","url":null,"abstract":"<p><p>Rif1 mediates telomere length, DNA replication, and DNA damage responses in budding yeast. Previous work identified several posttranslational modifications of Rif1, however none of these was shown to mediate the molecular or cellular responses to DNA damage, including telomere damage. We searched for such modifications using immunoblotting methods and the <i>cdc13-1</i> and <i>tlc1Δ</i> models of telomere damage. We found that Rif1 is phosphorylated during telomere damage, and that serines 57 and 110 within a novel phospho-gate domain (PGD) of Rif1 are important for this modification, in <i>cdc13-1</i> cells. The phosphorylation of Rif1 appeared to inhibit its accumulation on damaged chromosomes and the proliferation of cells with telomere damage. Moreover, we found that checkpoint kinases were upstream of this Rif1 phosphorylation and that the Cdk1 activity was essential for maintaining it. Apart from telomere damage, S57 and S110 were essential for Rif1 phosphorylation during the treatment of cells with genotoxic agents or during mitotic stress. We propose a speculative \"Pliers\" model to explain the role of the PGD phosphorylation during telomere and other types of damage.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 5","pages":"185-199"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5d/79/TMCB_43_2193768.PMC10184589.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9510818","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}

{"title":"The Insulin Receptor and Insulin like Growth Factor Receptor 5' UTRs Support Translation Initiation Independently of EIF4G1.","authors":"Nicholas K Clark, Meghan T Harris, William B Dahl, Zachary Knotts, Michael T Marr","doi":"10.1080/10985549.2023.2255120","DOIUrl":"10.1080/10985549.2023.2255120","url":null,"abstract":"<p><p>IRES mediated translation initiation requires a different repertoire of factors than canonical cap-dependent translation. Treatments that inhibit the canonical translation factor EIF4G1 have little or no effect on the ability of the Insr and Igf1r cellular IRESes to promote translation. Transcripts for two cellular receptors contain RNA elements that facilitate translation initiation without intact EIF4G1. Cellular IRES mechanisms may resemble viral type III IRESes allowing them to promote translate with a limited number of initiation factors allowing them to work under stress conditions when canonical translation is repressed.</p>","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"485-499"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41126269","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}