Cell Stress最新文献

{"title":"Biomechanical stress provides a second hit in the establishment of BMP/TGFβ-related vascular disorders.","authors":"Christian Hiepen,&nbsp;Jerome Jatzlau,&nbsp;Petra Knaus","doi":"10.15698/cst2020.02.213","DOIUrl":"https://doi.org/10.15698/cst2020.02.213","url":null,"abstract":"<p><p>Cardiovascular disorders are still the leading cause for mortality in the western world and challenge economies with steadily increasing healthcare costs. Understanding the precise molecular pathomechanisms behind and identifying players involved in the early onset of cardiovascular diseases remains crucial for the development of new therapeutic strategies. Taking advantage of CRISPR/Cas9 gene editing in human endothelial cells (ECs), we re-investigated the early molecular steps in a genetic vascular disorder termed pulmonary arterial hypertension (PAH) in our recent study (Hiepen C., Jatzlau J. <i>et al.</i>; PLOS Biol, 2019). Here, mutations in the Bone Morphogenetic Protein type II receptor (BMPR2) prime for the hereditary form (HPAH) with downregulated BMPR2 followed by a characteristic change in SMAD signaling, i.e. gain in both SMAD1/5 and SMAD2/3 responses. Remarkably these cells show increased susceptibility to signaling by TGFβ due to remodeling of the extracellular matrix (ECM) and increased biomechanics acting as a secondary stressor for ECs pathobiology. This clearly places BMPR2 not only as a BMP-signaling receptor, but also as a gatekeeper to protect ECs from excess TGFβ signaling.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 2","pages":"44-47"},"PeriodicalIF":6.4,"publicationDate":"2020-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37630156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACBP is an appetite stimulator across phylogenetic barriers.","authors":"Frank Madeo, Nektarios Tavernarakis, José M Bravo-San Pedro, Guido Kroemer","doi":"10.15698/cst2020.02.211","DOIUrl":"10.15698/cst2020.02.211","url":null,"abstract":"","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 2","pages":"27-29"},"PeriodicalIF":4.1,"publicationDate":"2020-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37630155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RPA and Pif1 cooperate to remove G-rich structures at both leading and lagging strand.","authors":"Laetitia Maestroni,&nbsp;Julien Audry,&nbsp;Pierre Luciano,&nbsp;Stéphane Coulon,&nbsp;Vincent Géli,&nbsp;Yves Corda","doi":"10.15698/cst2020.03.214","DOIUrl":"https://doi.org/10.15698/cst2020.03.214","url":null,"abstract":"<p><p>In <i>Saccharomyces cerevisiae</i>, the absence of Pif1 helicase induces the instability of G4-containing CEB1 minisatellite during leading strand but not lagging strand replication. We report that RPA and Pif1 cooperate to maintain CEB1 stability when the G4 forming strand is either on the leading or lagging strand templates. At the leading strand, RPA acts in the same pathway as Pif1 to maintain CEB1 stability. Consistent with this result, RPA co-precipitates with Pif1. This association between Pif1 and RPA is affected by the <i>rfa1-D228Y</i> mutation that lowers the affinity of RPA in particular for G-rich single-stranded DNA. At the lagging strand, in contrast to <i>pif1</i>Δ, the <i>rfa1-D228Y</i> mutation strongly increases the frequency of CEB1 rearrangements. We explain that Pif1 is dispensable at the lagging strand DNA by the ability of RPA by itself to prevent formation of stable G-rich secondary structures during lagging strand synthesis. Remarkably, overexpression of Pif1 rescues the instability of CEB1 at the lagging strand in the <i>rfa1-D228Y</i> mutant indicating that Pif1 can also act at the lagging strand. We show that the effects of the <i>rfa1-D228Y</i> (<i>rpa1-D223Y</i> in fission yeast) are conserved in <i>Schizosaccharomyces pombe</i>. Finally, we report that RNase H1 interacts in a DNA-dependent manner with RPA in budding yeast, however overexpression of RNase H1 does not rescue CEB1 instability observed in <i>pif1</i>Δ and <i>rfa1-D228Y</i> mutants. Collectively these results add new insights about the general role of RPA in preventing formation of DNA secondary structures and in coordinating the action of factors aimed at resolving them.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 3","pages":"48-63"},"PeriodicalIF":6.4,"publicationDate":"2020-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37753929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?","authors":"Olga Korenkova,&nbsp;Anna Pepe,&nbsp;Chiara Zurzolo","doi":"10.15698/cst2020.02.212","DOIUrl":"https://doi.org/10.15698/cst2020.02.212","url":null,"abstract":"<p><p>Intercellular communication is a fundamental property of multicellular organisms, necessary for their adequate responses to changing environment. Tunneling nanotubes (TNTs) represent a novel means of intercellular communication being a long cell-to-cell conduit. TNTs are actively formed under a broad range of stresses and are also proposed to exist under physiological conditions. Development is a physiological condition of particular interest, as it requires fine coordination. Here we discuss whether protrusions shown to exist during embryonic development of different species could be TNTs or if they represent other types of cell structure, like cytonemes or intercellular bridges, that are suggested to play an important role in development.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 2","pages":"30-43"},"PeriodicalIF":6.4,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37630157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kynurenine: an oncometabolite in colon cancer.","authors":"Niranjan Venkateswaran,&nbsp;Maralice Conacci-Sorrell","doi":"10.15698/cst2020.01.210","DOIUrl":"https://doi.org/10.15698/cst2020.01.210","url":null,"abstract":"<p><p>Tryptophan is one of the eight essential amino acids that must be obtained from the diet. Interestingly, tryptophan is the least abundant amino acid in most proteins, a large portion of cellular tryptophan is converted into metabolites of the serotonin and kynurenine pathways. In a recent study, (Venkateswaran, Lafita-Navarro et al., 2019, Genes Dev), we discovered that colon cancer cells display greater uptake and processing of tryptophan than normal colonic cells and tissues. This process is mediated by the oncogenic transcription factor MYC that promotes the expression of the tryptophan importers SLC1A5 and SLC7A5 and the tryptophan metabolizing enzyme AFMID. The metabolism of tryptophan in colon cancer cells generates kynurenine, a biologically active metabolite necessary to maintain continuous cell proliferation. Our results indicate that kynurenine functions as an oncometabolite, at least in part, by activating the transcription factor AHR, which then regulates growth promoting genes in cancer cells. We propose that blocking kynurenine production or activity can be an efficient approach to specifically limit the growth of colon cancer cells. Here, we describe our findings and new questions for future studies targeted at understanding AHR-independent function of kynurenine, as well as interfering with the enzyme AFMID as a new strategy to target the kynurenine pathway.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 1","pages":"24-26"},"PeriodicalIF":6.4,"publicationDate":"2020-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Necroptosis, tumor necrosis and tumorigenesis.","authors":"Zheng-Gang Liu,&nbsp;Delong Jiao","doi":"10.15698/cst2020.01.208","DOIUrl":"https://doi.org/10.15698/cst2020.01.208","url":null,"abstract":"<p><p>Necroptosis, known as programmed necrosis, is a form of caspase-independent, finely regulated cell death with necrotic morphology. Tumor necrosis, foci of necrotic cell death, occurs in advanced solid tumors and is often associated with poor prognosis of cancer patients. While it is well documented that apoptosis plays a key role in tumor regression and the inactivation of apoptosis is pivotal to tumor development, the role of necroptosis in tumorigenesis is still not fully understood as recent studies have reported both tumor-promoting and tumor-suppressing effects of necroptosis. In this short review, we will discuss some recent studies about the role of necroptosis in tumorigenesis and speculate the implications of these findings in future research and potential novel cancer therapy targeting necroptosis.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 1","pages":"1-8"},"PeriodicalIF":6.4,"publicationDate":"2019-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty acids - from energy substrates to key regulators of cell survival, proliferation and effector function.","authors":"Danilo Cucchi, Dolores Camacho-Muñoz, Michelangelo Certo, Valentina Pucino, Anna Nicolaou, Claudio Mauro","doi":"10.15698/cst2020.01.209","DOIUrl":"10.15698/cst2020.01.209","url":null,"abstract":"<p><p>Recent advances in immunology and cancer research show that fatty acids, their metabolism and their sensing have a crucial role in the biology of many different cell types. Indeed, they are able to affect cellular behaviour with great implications for pathophysiology. Both the catabolic and anabolic pathways of fatty acids present us with a number of enzymes, receptors and agonists/antagonists that are potential therapeutic targets, some of which have already been successfully pursued. Fatty acids can affect the differentiation of immune cells, particularly T cells, as well as their activation and function, with important consequences for the balance between anti- and pro-inflammatory signals in immune diseases, such as rheumatoid arthritis, psoriasis, diabetes, obesity and cardiovascular conditions. In the context of cancer biology, fatty acids mainly provide substrates for energy production, which is of crucial importance to meet the energy demands of these highly proliferating cells. Fatty acids can also be involved in a broader transcriptional programme as they trigger signals necessary for tumorigenesis and can confer to cancer cells the ability to migrate and generate distant metastasis. For these reasons, the study of fatty acids represents a new research direction that can generate detailed insight and provide novel tools for the understanding of immune and cancer cell biology, and, more importantly, support the development of novel, efficient and fine-tuned clinical interventions. Here, we review the recent literature focusing on the involvement of fatty acids in the biology of immune cells, with emphasis on T cells, and cancer cells, from sensing and binding, to metabolism and downstream effects in cell signalling.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"4 1","pages":"9-23"},"PeriodicalIF":6.4,"publicationDate":"2019-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37530151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress granules regulate paraspeckles: RNP granule continuum at work.","authors":"Haiyan An,&nbsp;Tatyana A Shelkovnikova","doi":"10.15698/cst2019.12.207","DOIUrl":"https://doi.org/10.15698/cst2019.12.207","url":null,"abstract":"<p><p>Eukaryotic cells contain several types of RNA-protein membraneless macro-complexes - ribonucleoprotein (RNP) granules that form by liquid-liquid phase separation. These structures represent biochemical microreactors for a variety of cellular processes and also act as highly accurate sensors of changes in the cellular environment. RNP granules share multiple protein components, however, the connection between spatially separated granules remains surprisingly understudied. Paraspeckles are constitutive nuclear RNP granules whose numbers significantly increase in stressed cells. Our recent work using affinity-purified paraspeckles revealed that another type of RNP granule, cytoplasmic stress granule (SG), acts as an important regulator of stress-induced paraspeckle assembly. Our study demonstrates that despite their residency in different cellular compartments, the two RNP granules are closely connected. This study suggests that nuclear and cytoplasmic RNP granules are integral parts of the intracellular \"RNP granule continuum\" and that rapid exchange of protein components within this continuum is important for the temporal control of cellular stress responses. It also suggests that cells can tolerate and efficiently handle a certain level of phase separation, which is reflected in the existence of \"bursts\", or \"waves\", of RNP granule formation. Our study triggers a number of important questions related to the mechanisms controlling the flow of RNP granule components within the continuum and to the possibility of targeting these mechanisms in human disease.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"3 12","pages":"385-387"},"PeriodicalIF":6.4,"publicationDate":"2019-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37453675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolism remodeling in pancreatic ductal adenocarcinoma.","authors":"Jin-Tao Li,&nbsp;Yi-Ping Wang,&nbsp;Miao Yin,&nbsp;Qun-Ying Lei","doi":"10.15698/cst2019.12.205","DOIUrl":"https://doi.org/10.15698/cst2019.12.205","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of death of patients with malignant cancers by 2030. Current options of PDAC treatment are limited and the five-year survival rate is less than 8%, leading to an urgent need to explore innovatively therapeutic strategies. PDAC cells exhibit extensively reprogrammed metabolism to meet their energetic and biomass demands under extremely harsh conditions. The metabolic changes are closely linked to signaling triggered by activation of oncogenes like <i>KRAS</i> as well as inactivation of tumor suppressors. Furthermore, tumor microenvironmental factors including extensive desmoplastic stroma reaction result in series of metabolism remodeling to facilitate PDAC development. In this review, we focus on the dysregulation of metabolism in PDAC and its surrounding microenvironment to explore potential metabolic targets in PDAC therapy.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"3 12","pages":"361-368"},"PeriodicalIF":6.4,"publicationDate":"2019-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37453674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LTX-315 – a promising novel antitumor peptide and immunotherapeutic agent","authors":"Dagmar Zweytick","doi":"10.15698/cst2019.11.202","DOIUrl":"https://doi.org/10.15698/cst2019.11.202","url":null,"abstract":"Host defense in mammals, as provided by the innate immune system, comprises proteins such as lactoferrin (LF), a multifunctional iron-binding glycoprotein originally discovered in bovine milk. LF is further pepsin-cleaved to a cationic amphipathic peptide, lactoferricin (LFcin; amino acid 1-45 of LF), which is known for its antimicrobial, antiseptic, antiviral, antitumor and immunomodulatory activities [13]. Bovine LFcin has been shown to inhibit liver and lung metastasis of both murine melanomas and lymphomas [4] and to induce apoptosis in human leukemic and carcinoma cell lines [5, 6]. LTX-315 [7] and LTX-302 [8], which derived of bovine LFcin by structural optimization, contain amongst others the non-coded residue β-diphenylalanine and show increased activity in vivo by peptide induced tumor regression and infiltration of the tumor by immune cells. LTX-315 is effective against multiple tumor types, and is therefore studied as novel immunotherapeutic agent in phase I/II clinical trials in combination with checkpoint inhibitors for treatment of advanced solid tumors, using the ability to reduce tumor growth and to induce de novo T-cell responses [9]. In the current issue of Cell Stress, Pittet and colleagues evaluated LTX-315 in conditional genetic mouse models of melanoma and sarcoma that are so far mainly resistant to standard treatment. Therefore, syngeneic grafts of murine melanoma B16F10, Brafand Pten-driven melanoma as well as Krasand P53-driven soft tissue sarcoma were studied in mice regarding their sensitivity towards LTX-315. These mutations are an ideal model, since they are often found in human patients suffering of these cancer types, as well are these tumor models, as also murine melanoma B16F10, poorly infiltrated by T cells and resistant to immune checkpoint therapy. The authors show a two-phase response in the tumor models triggered by the intratumoral injection with the peptide. The first phase of response is a rapid (within minutes) disruption of tumor vasculature and decrease of tumor burden. This direct antitumor effect seems to occur by induced cell lysis blocking the oxygen and nutrients supply by the tumor vasculature without the help of antitumor lymphocytes. The second phase of response is however as important for the antitumor (longterm) effect of the peptide. It endures over several weeks and is characterized by a tumor infiltration with CD8+ T cells that is normally very poor in the described tumor models and can display antitumor functions. Further, immune cells such as CD4+ T cells and natural killer (NK) cells were shown to migrate into the tumor environment upon treatment with LTX-315. This effect of triggering an antitumor immune response was more pronounced in the melanoma than in the sarcoma models, which might be due to the lower mutational load of the latter. However, this long-term conversion of a poorly to a highly immunogenic tumor promises a long-term antitumor immunity by prevention of tumor regrowth af","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"3 1","pages":"328 - 329"},"PeriodicalIF":6.4,"publicationDate":"2019-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43874510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}