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To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.
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Proliferación Celular , Fibroblastos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/biosíntesis , Presión Osmótica , Biosíntesis de Proteínas , Ribosomas/metabolismo , Adaptación Fisiológica , Adenosina Trifosfato/metabolismo , Animales , Codón Iniciador , Fibroblastos/patología , Células HEK293 , Humanos , Cinética , Ratones , Mitocondrias/genética , Mitocondrias/patología , Proteínas Mitocondriales/genética , Ribosomas/genética , Transducción de SeñalRESUMEN
The advent of PD1/PD-L1 inhibitors has significantly transformed the therapeutic landscape for clear cell renal cell carcinoma (ccRCC). This review provides an in-depth analysis of the biological functions and regulatory mechanisms of PD1 and PD-L1 in ccRCC, emphasizing their role in tumor immune evasion. We comprehensively evaluate the clinical efficacy and safety profiles of PD1/PD-L1 inhibitors, such as Nivolumab and Pembrolizumab, through a critical examination of recent clinical trial data. Furthermore, we discuss the challenges posed by resistance mechanisms to these therapies and potential strategies to overcome them. We also explores the synergistic potential of combination therapies, integrating PD1/PD-L1 inhibitors with other immunotherapies, targeted therapies, and conventional modalities such as chemotherapy and radiotherapy. In addition, we examine emerging predictive biomarkers for response to PD1/PD-L1 blockade and biomarkers indicative of resistance, providing a foundation for personalized therapeutic approaches. Finally, we outline future research directions, highlighting the need for novel therapeutic strategies, deeper mechanistic insights, and the development of individualized treatment regimens. Our work summarizes the latest knowledge and progress in this field, aiming to provide a valuable reference for improving clinical efficacy and guiding future research on the application of PD1/PD-L1 inhibitors in ccRCC.
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Antígeno B7-H1 , Carcinoma de Células Renales , Inhibidores de Puntos de Control Inmunológico , Neoplasias Renales , Receptor de Muerte Celular Programada 1 , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/terapia , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Biomarcadores de Tumor , Resultado del Tratamiento , Animales , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Inmunoterapia/métodosRESUMEN
Most aspects of RNA metabolism involve DEAD-box RNA helicases, enzymes that bind and remodel RNA and RNA-protein complexes in an ATP-dependent manner. Here we show that the DEAD-box helicase Ded1p oligomerizes in the cell and in vitro, and unwinds RNA as a trimer. Two protomers bind the single-stranded region of RNA substrates and load a third protomer to the duplex, which then separates the strands. ATP utilization differs between the strand-separating protomer and those bound to the single-stranded region. Binding of the eukaryotic initiation factor 4G to Ded1p interferes with oligomerization and thereby modulates unwinding activity and RNA affinity of the helicase. Our data reveal a strict division of labor between the Ded1p protomers in the oligomer. This mode of oligomerization fundamentally differs from other helicases. Oligomerization represents a previously unappreciated level of regulation for DEAD-box helicase activities.
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ARN Helicasas DEAD-box/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/enzimología , Adenosina Trifosfato/química , Biocatálisis , ARN Helicasas DEAD-box/fisiología , Hidrólisis , Unión Proteica , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Subunidades de Proteína/química , ARN Bicatenario/química , Proteínas de Saccharomyces cerevisiae/fisiologíaRESUMEN
The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H2S has been shown to persulfidate redox sensitive cysteine residues resulting in an H2S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H2S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTSGS). We propose that the RTSGS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.
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Metabolismo Energético , Compuestos de Sulfhidrilo/metabolismo , Factor de Transcripción Activador 4/metabolismo , Animales , Bioensayo , Biotina/metabolismo , Línea Celular , Cisteína/metabolismo , Disulfuros/metabolismo , Glucólisis , Hepatocitos/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Células Secretoras de Insulina/metabolismo , Espectrometría de Masas , Análisis de Flujos Metabólicos , Mitocondrias/metabolismo , Oxidación-Reducción , Proteoma/metabolismo , Proteómica , Ratas , Sulfuros/metabolismoRESUMEN
Asymmetric reductive amination (ARA) is one of the most promising methods for the synthesis of chiral amines. Herein we report our efforts on merging two ARA reactions into a single-step transformation. Catalyzed by a complex formed from iridium and a steric hindered phosphoramidite, readily available and inexpensive aromatic ketones initially undergo the first ARA with ammonium acetate to afford primary amines, which serve as the amine sources for the second ARA, and finally provide the enantiopure C2 -symmetric secondary amine products. The developed process competently enables the successive coupling of inorganic and organic nitrogen sources with ketones in the same reaction system. The Brønsted acid additive plays multiple roles in this procedure: it accelerates the formation of imine intermediates, minimizes the inhibitory effect of N-containing species on the iridium catalyst, and reduces the primary amine side products.
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Owing to the high mobility, narrow bandgap, strong spin-orbit coupling and large g-factor, Sb-based III-V nanowires (NWs) attracted significant interests in high speed electronics, long-wavelength photodetectors and quantum superconductivity in the past decade. In this review, we aim to give an integrated summarization about the recent advances in binary as well as ternary Sb-based III-V NWs, starting from the fundamental properties, NWs growth mechanism, typical synthetic methods to their applications in transistors, photodetectors, and Majorana fermions detection. Up to now, famous NWs growth techniques of solid-source chemical vapor deposition (CVD), molecular beam epitaxy, metal organic vapor phase epitaxy and metal organic CVD etc have been adopted and developed for the controllable growth of Sb-based III-V NWs. Several parameters including heating temperature, III/V ratio of source materials, growth temperature, catalyst size and kinds, and growth substrate play important roles on the morphology, position, diameter distribution, growth orientation and crystal phase of Sb-based III-V NWs. Furthermore, we discuss the photoelectrical applications of Sb-based III-V NWs such as field-effect-transistors, tunnel diode, low-power inverter, and infrared detectors etc. Importantly, due to the strongest spin-orbit interaction and giant g-factor among all III-V semiconductors, InSb with the geometry of one-dimension NW is considered as the most promising candidate for the detection of Majorana fermions. In the end, we also summarize the main challenges remaining in the field and put forward some suggestions for the future development of Sb-based III-V NWs.
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The translation, localization, and degradation of cytoplasmic mRNAs are controlled by the formation and rearrangement of their mRNPs. The conserved Ded1/DDX3 DEAD-box protein functions in an unknown manner to affect both translation initiation and repression. We demonstrate that Ded1 first functions by directly interacting with eIF4G to assemble a Ded1-mRNA-eIF4F complex, which accumulates in stress granules. After ATP hydrolysis by Ded1, the mRNP exits stress granules and completes translation initiation. Thus, Ded1 functions both as a repressor of translation, by assembling an mRNP stalled in translation initiation, and as an ATP-dependent activator of translation, by resolving the stalled mRNP. These results identify Ded1 as a translation initiation factor that assembles and remodels an intermediate complex in translation initiation.
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ARN Helicasas DEAD-box/fisiología , Factor 4F Eucariótico de Iniciación/metabolismo , Biosíntesis de Proteínas , ARN Mensajero/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiología , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Gránulos Citoplasmáticos/metabolismo , ARN Helicasas DEAD-box/química , ARN Helicasas DEAD-box/metabolismo , Factor 4G Eucariótico de Iniciación/metabolismo , Regulación de la Expresión Génica , Modelos Genéticos , Datos de Secuencia Molecular , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/fisiología , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Alineación de SecuenciaRESUMEN
Four new (1-4), along with six known (5-10) dihydro-ß-agarofuran sesquiterpene polyesters were isolated from the whole plants of Parnassia wightiana. The new compounds were structurally elucidated through spectroscopic analysis including UV (Ultraviolet Spectrum), IR (Infrared Spectrum), ¹H-NMR (¹Hydrogen-Nuclear Magnetic Resonance), ¹³C-NMR (¹³Carbon-Nuclear Magnetic Resonance), DEPT (Distortionless Enhancement by Polarization Transfer), ¹H-¹H COSY (¹H-¹H Correlation Spectroscopy), HSQC (Heteronuclear Single Quantum Coherence), HMBC (Heteronuclear Multiple Bond Correlation), NOESY (Nuclear Overhauser Enhancement Spectroscopy) and HR-MS (High Resolution Mass Specttrum) and their absolute configurations were proposed by comparison of NOESY spectra and specific optical rotations with those of known compounds and biosynthesis grounds. Compound 2 is the first sesquiterpene alkaloid isolated from this plant. New compounds 1-4 exhibited some cytotoxic activities against NB4, MKN-45 and MCF-7 cells at 20 µM and of which 4 showed the highest activity against NB4 and MKN-45 cells with inhibition rates of 85.6% and 30.5%, respectively.
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Poliésteres/química , Sesquiterpenos/química , Streptophyta/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Extractos Vegetales/químicaRESUMEN
The interaction between the immune system and the tumor matrix has a huge impact on the progression and treatment of cancer. This paper summarizes and discusses the crosstalk between T cells and cancer-associated fibroblasts (CAFs). CAFs can also produce inhibitors that counteract the function of T cells and promote tumor immune escape, while T cells can also engage in complex two-way interactions with CAFs through direct cell contact, the exchange of soluble factors such as cytokines, and the remodeling of the extracellular matrix. Precise targeted intervention can effectively reverse tumor-promoting crosstalk between T cells and CAFs, improve anti-tumor immune response, and provide a new perspective for cancer treatment. Therefore, it is important to deeply understand the mechanism of crosstalk between T cells and CAFs. This review aims to outline the underlying mechanisms of these interactions and discuss potential therapeutic strategies that may become fundamental tools in the treatment of cancer, especially hard-to-cure cancers.
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Fibroblastos Asociados al Cáncer , Neoplasias , Linfocitos T , Microambiente Tumoral , Humanos , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Animales , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/patología , Comunicación Celular , Escape del Tumor/efectos de los fármacos , Citocinas/metabolismo , Citocinas/inmunología , Matriz Extracelular/metabolismoRESUMEN
BACKGROUND: Intraductal papillary neoplasms of the bile duct (IPNBs) are rare and characterized by papillary growth within the bile duct lumen. IPNB is similar to obstructive biliary pathology. In this report, we present an unexpected case of asymptomatic IPNB and consolidate our findings with the relevant literature to augment our understanding of this condition. Integrating relevant literature contributes to a more comprehensive understanding of the disease. CASE SUMMARY: A 66-year-old Chinese male patient was admitted to our hospital for surgical intervention after gallstones were discovered during a routine physical examination. Preoperative imaging revealed a lesion on the left side of the liver, which raised the suspicion of IPNB. A laparoscopic left hemihepatectomy was performed, and subsequent histopathological examination confirmed the diagnosis of IPNB. At the 3-mo postoperative follow-up, the patient reported good recovery and no metastasis. IPNB can manifest both latently and asymptomatically. Radical surgical resection is the most effective treatment for IPNB. CONCLUSION: Hepatic and biliary masses, should be considered to diagnose IPNB. Prompt surgery and vigilant follow-up are crucial in determining prognosis.
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Clear cell renal cell carcinoma (ccRCC) is a common kidney cancer with subtle early symptoms, high recurrence rates, and low sensitivity to traditional treatments like radiotherapy and chemotherapy. Identifying novel therapeutic targets is critical. The expression level of adenylate kinases 7 (AK7) in ccRCC was examined by the TCGAportal and UALCAN databases. The effect of AK7 on proliferation, invasion and migration of ccRCC cell lines was evaluated by cell assay. The correlation between AK7 expression and prognosis, as well as its direct relationship with immunotherapy efficacy, was analyzed using CANCERTOOL and Kaplan-Meier plotter data. Moreover, the TISIDB database was used to study the relationship between AK7 and immune markers. The effect of overexpressed AK7 combined with PD1 monoclonal antibody on ccRCC was evaluated in animal experiments. The results showed that low level of AK7 expression was observed in ccRCC tissues. The expression of AK7 can regulate the proliferation, invasion, and migration of human ccRCC cell lines. The level of AK7 expression was associated with OS of ccRCC patients. This was potentially due to the negative connection between AK7 expression and CD8+ T cell depletion, indicating that immunotherapy might be less effective in individuals with low AK7 expression. Conversely, augmenting AK7 demonstrated an enhanced effectiveness of anti-PD1 therapy. The findings of our research strongly indicated that AK7 could serve as both a prognostic indicator and therapeutic target for patients with ccRCC. Moreover, the overexpression of AK7 combined with anti-PD1 held promising potential as a therapeutic approach for treating ccRCC.
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Carcinoma de Células Renales , Inmunoterapia , Neoplasias Renales , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias Renales/inmunología , Neoplasias Renales/terapia , Neoplasias Renales/patología , Neoplasias Renales/genética , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Animales , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inmunoterapia/métodos , Ratones , Proliferación Celular/efectos de los fármacos , Movimiento Celular , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Progresión de la Enfermedad , Pronóstico , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cholangiocarcinoma (CCA), a rare yet notably aggressive cancer, has experienced a surge in incidence in recent years. Presently, surgical resection remains the most effective curative strategy for CCA. Nevertheless, a majority of patients with CCA are ineligible for surgical removal at the time of diagnosis. For advanced stages of CCA, the combination of gemcitabine and cisplatin is established as the standard chemotherapy regimen. Despite this, treatment efficacy is often hindered by the development of resistance. In recent times, immune checkpoint inhibitors, particularly those that block programmed death 1 and its ligand (PD1/PD-L1), have emerged as promising strategies against a variety of cancers and are being increasingly integrated into the therapeutic landscape of CCA. A growing body of research supports that the use of PD1/PD-L1 monoclonal antibodies in conjunction with chemotherapy may significantly improve patient outcomes. This article seeks to meticulously review the latest studies on PD1/PD-L1 involvement in CCA, delving into their expression profiles, prognostic significance, contribution to oncogenic processes, and their potential clinical utility.
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Antígeno B7-H1 , Neoplasias de los Conductos Biliares , Colangiocarcinoma , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Receptor de Muerte Celular Programada 1 , Colangiocarcinoma/terapia , Colangiocarcinoma/inmunología , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Humanos , Antígeno B7-H1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias de los Conductos Biliares/terapia , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , AnimalesRESUMEN
BACKGROUND: The molecular targets and associated mechanisms of hepatocellular carcinoma (HCC) have been widely studied, but the roles of PDZK1 in HCC are unclear. Therefore, the aim of this study is to explore the role and associated mechanisms of PDZK1 in HCC. RESULTS: It was found that the expression of PDZK1 in HCC tissues was higher than that in paired paracancerous tissues. High expression of PDZK1 was associated with lymph node metastasis, degree of differentiation, and clinical stage. Upregulation of PDZK1 in HCC cells affected their proliferation, migration, invasion, apoptosis, and cell cycle, and also induced PI3K/AKT activation. PDZK1 is a downstream target gene of miR-101-3p. Accordingly, increase in the expression of miR-101-3p reversed the promotive effect of PDZK1 in HCC. Moreover, PDZK1 was found to accelerate cell proliferation and promote the malignant progression of HCC via the PI3K/AKT pathway. CONCLUSION: Our study indicated that the miR-101-3p/PDZK1 axis plays a role in HCC progression and could be beneficial as a novel biomarker and new therapeutic target for HCC treatment.
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We focus on investigating the role of Parthenolide (Par), a small sesquiterpenoid molecule, in hepatocellular carcinoma (HCC) and its effective target.Highly-metastatic HCC cells, MHCC97-H, were divided into the DMSO and the Par groups, of which the Par group was intervened at 5 and 10 mg/L doses. Cell viability was assessed by CCK-8 assay. Transwell chamber assay was performed to examine the metastatic and invasive abilities, while plate clone formation assay was conducted to detect the clone formation ability. For analysis of glucose uptake, glycolytic ability and lactate level, the glycolysis assay was employed. Brdu staining was performed to evaluate the cell proliferative potential. The P50 and HIF-1α levels were measured by immunofluorescence, while the expressions of p-P50 and HIF-1α were determined by Western-Blot. Small molecule-protein docking and Pull-down experiments were conducted to validate the Par-P50 binding model. After establishing the tumor-bearing mouse model, Par was administered by gavage to measure the tissue levels of P50 and HIF-1α, followed by plotting of tumor growth curves.Par could inhibit the metastatic, invasive and clone formation abilities of MHCC97-H cells, reduce the cell proliferative potential, and suppress the glycolysis, as manifested by down-regulated level of lactate and reduced oxygen consumption. Meanwhile, Par inhibited the HIF-1α expression. We found that after silencing P50, the HIF-1α was down-regulated, the glycolytic ability decreased drastically, and the cellular metastatic and invasive abilities were suppressed. After P50 knockout, the effect of Par intervention on the MHCC97-H cells was reduced. In HCC-bearing mice, Par also exhibited an excellent anti-tumor effect, decreasing the tissue levels of P50 and HIF-1α.This study discovers that Par can inhibit the HIF-1α-mediated glycolysis of HCC cells by targeting P50, thereby exerting an anti-tumor effect. P50 is a major effective target of Par.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Sesquiterpenos , Ratones , Animales , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , FN-kappa B/metabolismo , Sesquiterpenos/farmacología , Subunidad alfa del Factor 1 Inducible por Hipoxia , Lactatos , Línea Celular TumoralRESUMEN
BACKGROUND: Gastric cancer (GC) is one of the leading malignancies of the digestive system. Circular RNAs (circRNAs) are well-established to play critical regulatory roles in GC development. The current study sought to explore the effects and regulatory mechanism of circ_0001013 in the course of GC. METHODS: First, differential circRNAs and related mechanisms in GC were predicted by microarray analysis. Circ_0001013, microRNA (miR)-136, and TWSG1 expression patterns were subsequently detected in GC clinical samples and cells using RT-qPCR. The relationship among circ_0001013, miR-136, and TWSG1 was further assessed by dual-luciferase reporter assay, biotin-coupled probe pull-down assay, and biotin-coupled miRNA capture. Based on gain- and loss-of-function assays, GC cell proliferation, migration, invasion, and the cell cycle and apoptosis were also measured by 5-ethynyl-2'-deoxyuridine (EdU) assay, scratch test, Transwell assay, and flow cytometry, respectively. Moreover, the effect of circ_0001013 on tumor growth was detected by tumor xenografting in nude mice. RESULTS: Circ_0001013 was predicted to be up-regulated in GC by microarray profiling, which was confirmed by RT-qPCR detection in GC tissues and cells. miR-136 was poorly expressed, and TWSG1 was highly expressed in GC tissues. Mechanistically, circ_0001013 bound to miR-136, which negatively targeted TWSG1 in the GC cells. Silencing circ_0001013 or TWSG1 or over-expressing miR-136 led to decreased GC cell proliferation, migration, invasion, and cell cycle arrest and enhanced apoptosis. Furthermore, silencing circ_0001013 resulted in diminished TWSG1 expression and inhibited transplanted tumor growth in the nude mice. CONCLUSION: Collectively, our findings indicated that circ_0001013 increased TWSG1 expression by binding to miR-136, thereby exerting oncogenic effects in GC.
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Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCFFbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCFFbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCFFbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCFFbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCFFbxo4-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.
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Carcinogénesis , Ribonucleoproteína Heterogénea-Nuclear Grupo K , Humanos , Ribonucleoproteína Heterogénea-Nuclear Grupo K/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo K/metabolismo , Carcinogénesis/genética , Ubiquitinación , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Oncogenes , ARN Mensajero/metabolismoRESUMEN
Pancreatic ß-cells are prone to endoplasmic reticulum (ER) stress due to their role in insulin secretion. They require sustainable and efficient adaptive stress responses to cope with this stress. Whether episodes of chronic stress directly compromise ß-cell identity is unknown. We show here under reversible, chronic stress conditions ß-cells undergo transcriptional and translational reprogramming associated with impaired expression of regulators of ß-cell function and identity. Upon recovery from stress, ß-cells regain their identity and function, indicating a high degree of adaptive plasticity. Remarkably, while ß-cells show resilience to episodic ER stress, when episodes exceed a threshold, ß-cell identity is gradually lost. Single cell RNA-sequencing analysis of islets from type 1 diabetes patients indicates severe deregulation of the chronic stress-adaptation program and reveals novel biomarkers of diabetes progression. Our results suggest ß-cell adaptive exhaustion contributes to diabetes pathogenesis.
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Plasticidad de la Célula , Células Secretoras de Insulina , Adaptación Fisiológica , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/genética , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismoRESUMEN
The integrated stress response (ISR) plays a pivotal role in adaptation of translation machinery to cellular stress. Here, we demonstrate an ISR-independent osmoadaptation mechanism involving reprogramming of translation via coordinated but independent actions of mTOR and plasma membrane amino acid transporter SNAT2. This biphasic response entails reduced global protein synthesis and mTOR signaling followed by translation of SNAT2. Induction of SNAT2 leads to accumulation of amino acids and reactivation of mTOR and global protein synthesis, paralleled by partial reversal of the early-phase, stress-induced translatome. We propose SNAT2 functions as a molecular switch between inhibition of protein synthesis and establishment of an osmoadaptive translation program involving the formation of cytoplasmic condensates of SNAT2-regulated RNA-binding proteins DDX3X and FUS. In summary, we define key roles of SNAT2 in osmotolerance.
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Sistema de Transporte de Aminoácidos A , Aminoácidos , Sistema de Transporte de Aminoácidos A/genética , Sistema de Transporte de Aminoácidos A/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Aminoácidos/metabolismo , Biosíntesis de Proteínas , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The title compound, C(16)H(14)Cl(2)O(4)S, was obtained by the reaction of eugenol (4-allyl-2-meth-oxy-phenol) and 3,4-dichloro-benzene-sulfonyl chloride. The dihedral angle between the benzene rings in the mol-ecule is 40.53â (4)°. No significantly short inter-molecular contacts are observed in the crystal structure.
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G-quadruplex DNA interacts with the N-terminal intrinsically disordered domain of the DEAD-box helicase Ded1p, diminishing RNA unwinding activity but enhancing liquid-liquid phase separation of Ded1p in vitro and in cells. The data highlight multifaceted effects of quadruplex DNA on an enzyme with intrinsically disordered domains.