RESUMEN
Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.
Asunto(s)
Proteína que Contiene Valosina , Proteína que Contiene Valosina/metabolismo , Proteína que Contiene Valosina/genética , Proteína que Contiene Valosina/química , Humanos , Multimerización de Proteína , Animales , Mutación , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/química , Osteítis Deformante/genética , Osteítis Deformante/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/química , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Distrofia Muscular de CinturasRESUMEN
Cardiac fibrosis is a commonly seen pathophysiological process in various cardiovascular disorders, such as coronary heart disorder, hypertension, and cardiomyopathy. Cardiac fibroblast trans-differentiation into myofibroblasts (MFs) is a key link in myocardial fibrosis. LncRNA PVT1 participates in fibrotic diseases in multiple organs; however, its role and mechanism in cardiac fibrosis remain largely unknown. Human cardiac fibroblasts (HCFs) were stimulated with TGF-ß1 to induce myofibroblast; Immunofluorescent staining, Immunoblotting, and fluorescence in situ hybridization were used to detect the myofibroblasts phenotypes and lnc PVT1 expression. Cell biological phenotypes induced by lnc PVT1 knockdown or overexpression were detected by CCK-8, flow cytometry, and Immunoblotting. A mouse model of myocardial fibrosis was induced using isoproterenol (ISO), and the cardiac functions were examined by echocardiography measurements, cardiac tissues by H&E, and Masson trichrome staining. In this study, TGF-ß1 induced HCF transformation into myofibroblasts, as manifested as significantly increased levels of α-SMA, vimentin, collagen I, and collagen III; the expression level of lnc PVT1 expression showed to be significantly increased by TGF-ß1 stimulation. The protein levels of TGF-ß1, TGFBR1, and TGFBR2 were also decreased by lnc PVT1 knockdown. Under TGF-ß1 stimulation, lnc PVT1 knockdown decreased FN1, α-SMA, collagen I, and collagen III protein contents, inhibited HCF cell viability and enhanced cell apoptosis, and inhibited Smad2/3 phosphorylation. Lnc PVT1 positively regulated MYC expression with or without TGF-ß1 stimulation; MYC overexpression in TGF-ß1-stimulated HCFs significantly attenuated the effects of lnc PVT1 knockdown on HCF proliferation and trans-differentiation to MFs. In the ISO-induced myocardial fibrosis model, lnc PVT1 knockdown partially reduced fibrotic area, improved cardiac functions, and decreased the levels of fibrotic markers. In addition, lnc PVT1 knockdown decreased MYC and CDK4 levels but increased E-cadherin in mice heart tissues. lnc PVT1 is up-regulated in cardiac fibrosis and TGF-ß1-stimulated HCFs. Lnc PVT1 knockdown partially ameliorates TGF-ß1-induced HCF activation and trans-differentiation into MFs in vitro and ISO-induced myocardial fibrosis in vivo, potentially through interacting with MYC and up-regulating MYC.
RESUMEN
Aberrant activation of RAS/MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in an SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS/MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.
Asunto(s)
Autofagia , Proteína Tirosina Fosfatasa no Receptora Tipo 11 , Proteínas ras , Animales , Humanos , Ratones , Regulación Alostérica/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas ras/metabolismo , Proteínas ras/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) control protein tyrosine phosphorylation and regulate numerous cellular functions. Dysregulated PTP activity is associated with the onset of multiple human diseases. Nevertheless, understanding of the physiological function and disease biology of most PTPs remains limited, largely due to the lack of PTP-specific chemical probes. In this study, starting from a well-known nonhydrolyzable phosphotyrosine (pTyr) mimetic, phosphonodifluoromethyl phenylalanine (F2Pmp), we synthesized 7 novel phosphonodifluoromethyl-containing bicyclic/tricyclic aryl derivatives with improved cell permeability and potency toward various PTPs. Furthermore, with fragment- and structure-based design strategies, we advanced compound 9 to compound 15, a first-in-class, potent, selective, and bioavailable inhibitor of human CDC14A and B phosphatases. This study demonstrates the applicability of the fragment-based design strategy in creating potent, selective, and bioavailable PTP inhibitors and provides a valuable probe for interrogating the biological roles of hCDC14 phosphatases and assessing their potential for therapeutic interventions.
Asunto(s)
Inhibidores Enzimáticos , Fosfotirosina , Humanos , Fosfotirosina/metabolismo , Fosfotirosina/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Proteínas Tirosina Fosfatasas no Receptoras/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/química , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/metabolismo , Estructura Molecular , Disponibilidad BiológicaRESUMEN
Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19-related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor-mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B, the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A, the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic-based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.
Asunto(s)
Síndrome de Activación Macrofágica , MicroARNs , Humanos , Animales , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Receptores de IgG/genética , Síndrome de Activación Macrofágica/genética , Fagocitosis/genética , Interleucina-12RESUMEN
During embryonic development, blood cells emerge from specialized endothelial cells, named haemogenic endothelial cells (HECs). As HECs are rare and only transiently found in early developing embryos, it remains difficult to distinguish them from endothelial cells. Here we performed transcriptomic analysis of 28- to 32-day human embryos and observed that the expression of Fc receptor CD32 (FCGR2B) is highly enriched in the endothelial cell population that contains HECs. Functional analyses using human embryonic and human pluripotent stem cell-derived endothelial cells revealed that robust multilineage haematopoietic potential is harboured within CD32+ endothelial cells and showed that 90% of CD32+ endothelial cells are bona fide HECs. Remarkably, these analyses indicated that HECs progress through different states, culminating in FCGR2B expression, at which point cells are irreversibly committed to a haematopoietic fate. These findings provide a precise method for isolating HECs from human embryos and human pluripotent stem cell cultures, thus allowing the efficient generation of haematopoietic cells in vitro.
Asunto(s)
Desarrollo Embrionario , Hematopoyesis , Receptores de IgG , Humanos , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Embrión de Mamíferos/metabolismo , Embrión de Mamíferos/citología , Desarrollo Embrionario/genética , Células Endoteliales/metabolismo , Células Endoteliales/citología , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica , Hemangioblastos/metabolismo , Hemangioblastos/citología , Hematopoyesis/genética , Células Madre Embrionarias Humanas/metabolismo , Células Madre Embrionarias Humanas/citología , Células Madre Pluripotentes/metabolismo , Células Madre Pluripotentes/citología , Receptores de IgG/metabolismo , Receptores de IgG/genética , TranscriptomaRESUMEN
Comprehension of metaphorical expressions differs with their degree of novelty. Conventional metaphors are typically comprehended as easily as literal sentences, while novel metaphors are responded to less quickly than their conventional counterparts. However, the influence of metaphor signals on the interpretability and acceptability of sentences with metaphors, especially their potential interaction with novelty, remains an open question. We conducted six online experiments among 1,694 native speakers of American English to examine how interpretability and acceptability ratings of individually presented sentences were affected by metaphor novelty and different types of metaphor signals. Across all six experiments, we consistently found that novel metaphors decreased the interpretability and acceptability of sentences compared to both conventional metaphors and literal controls. Signals, on the contrary, did not impact the interpretability or acceptability of the sentences. Moreover, only in experiment 3b did we find an interaction between metaphor type and signals. Specifically, when a metaphor was marked by double signals (i.e., both lexical signals and a typographical signal were added around the metaphorical keywords) vs. no signals, acceptability of novel metaphors increased, but acceptability of conventional metaphors decreased. We hypothesize that the double signaling of novel metaphors marks their novelty, making them more acceptable. By contrast, the double signaling of conventional metaphors may have been perceived as redundant, leading to a lower acceptability.
Asunto(s)
Metáfora , HumanosRESUMEN
INTRODUCTION: Phosphatase of regenerating liver (PRL) family proteins, also known as protein tyrosine phosphatase 4A (PTP4A), have been implicated in many types of cancers. The PRL family of phosphatases consists of three members, PRL1, PRL2, and PRL3. PRLs have been shown to harbor oncogenic potentials and are highly expressed in a variety of cancers. Given their roles in cancer progression and metastasis, PRLs are potential targets for anticancer therapies. However, additional studies are needed to be performed to fully understand the roles of PRLs in blood cancers. AREAS COVERED: In this review, we will summarize recent studies of PRLs in normal and malignant hematopoiesis, the role of PRLs in regulating various signaling pathways, and the therapeutic potentials of targeting PRLs in hematological malignancies. We will also discuss how to improve current PRL inhibitors for cancer treatment. EXPERT OPINION: Although PRL inhibitors show promising therapeutic effects in preclinical studies of different types of cancers, moving PRL inhibitors from bench to bedside is still challenging. More potent and selective PRL inhibitors are needed to target PRLs in hematological malignancies and improve treatment outcomes.
Asunto(s)
Antineoplásicos , Neoplasias Hematológicas , Terapia Molecular Dirigida , Proteínas Tirosina Fosfatasas , Transducción de Señal , Humanos , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Proteínas Tirosina Fosfatasas/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Desarrollo de Medicamentos , Proteínas de la Membrana , Proteínas de Ciclo CelularRESUMEN
Natural products have been playing indispensable roles in the development of lifesaving drug molecules. They are also valuable sources for covalent protein modifiers. However, they often are scarce in nature and have complex chemical structures, which are limiting their further biomedical development. Thus, natural product-inspired small molecules which still contain the essence of the parent natural products but are readily available and amenable for structural modification, are important and desirable in searching for lead compounds for various disease treatment. Inspired by the complex and diverse ent-kaurene diterpenoids with significant biological activities, we have created a synthetically accessible and focused covalent library by incorporating the bicyclo[3.2.1]octane α-methylene ketone, which is considered as the pharmacophore of ent-kaurene diterpenoids, as half of the structure, and replacing the other half with much less complex but more druglike scaffolds. From this library, we have identified and characterized selective covalent inhibitors of protein tyrosine phosphatase SHP2, an important anti-cancer therapeutic target. The success of this study demonstrated the importance of creating and evaluating natural product-inspired library as well as their application in targeting challenging disease targets.
RESUMEN
The activities of the phospholipase C gamma (PLCγ) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLCγ1 or PLCγ2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLCγ family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLCγ1 and PLCγ2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLCγ family of enzymes.
Asunto(s)
Colorantes Fluorescentes , Fosfatidilinositoles , Fosfolipasa C gamma , Hidrolasas Diéster Fosfóricas , Cumarinas/farmacología , Fosfolipasas de Tipo CRESUMEN
The contribution of urban non-point source (NPS) pollution to surface water pollution has gradually increased, analyzing the sources of urban NPS pollution is of great significance for precisely controlling surface water pollution. A bibliometric analysis of relevant research literature from 2000 to 2021 reveals that the main methods used in the source analysis research of urban NPS pollution include the emission inventory approach, entry-exit mass balance approach, principal component analysis (PCA), positive matrix factorization (PMF) model, etc. These methods are primarily applied in three aspects: source analysis of rainfall-runoff pollution, source analysis of wet weather flow (WWF) pollution in combined sewers, and analysis of the contribution of urban NPS to the surface water pollution load. The application of source analysis methods in urban NPS pollution research has demonstrated an evolution from qualitative to quantitative, and further towards precise quantification. This progression has transitioned from predominantly relying on on-site monitoring to incorporating model simulations and employing mathematical statistical analyses for traceability. This paper reviews the principles, advantages, disadvantages, and the scope of application of these methods. It also aims to address existing problems and analyze potential future development directions, providing valuable references for subsequent related research.
Asunto(s)
Contaminación Difusa , Contaminantes Químicos del Agua , Contaminación Difusa/análisis , Monitoreo del Ambiente/métodos , Contaminación del Agua/análisis , Tiempo (Meteorología) , China , Contaminantes Químicos del Agua/análisisRESUMEN
OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.
Asunto(s)
Medicamentos Herbarios Chinos , Gastritis Atrófica , Infecciones por Helicobacter , Helicobacter pylori , Lesiones Precancerosas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Gastritis Atrófica/tratamiento farmacológico , Gastritis Atrófica/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/tratamiento farmacológico , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/patología , Metaplasia , Ácido Fólico/uso terapéutico , Mucosa Gástrica/patologíaRESUMEN
OBJECTIVES: To observe the effect of catgut embedding at "Feishu"(BL13), "Dingchuan" (EX-B1) and "Danzhong" (CV17) on expression of phosphorylated p38 mitogen activated protein kinase (p-p38 MAPK), interleukin-4 (IL-4), interferon-γ (IFN-γ) and changes of airway epithelial cells (AEC) in the lung tissue of bronchial asthma (BA) rats, so as to explore its mechanisms underlying improvement of BA. METHODS: Forty male Wistar rats were randomly and equally divided into blank control, model, dexamethasone (DEX) and catgut embedding groups. The BA model was established by intraperitoneal injection of suspension of ovalbumin and aluminum hydroxide. Rats of the DEX group received intraperitoneal injection of DEX (1.5 mg/kg), once daily for 2 weeks, and those of the catgut embedding group received catgut embedding at BL13, EX-B1 and CV17 only one time. The rats' sneezing times per miniute in each group were recorded. H.E. staining was used to observe the histopathological changes of the lung tissue under light microscope. A transmission electron microscope (TEM) was used to observe the ultrastructural changes of AEC in the lung tissue, including the thickness of bronchial wall and bronchial smooth muscle by using an image analysis software. The protein expressions of p-p38 MAPK, IL-4 and INF-γ in the lung tissue were determined using Western blot. RESULTS: Morphological observation revealed that in the model group, light microscope showed deformed and swollen bronchial tube wall with increased folds and thickened bronchial smooth muscleï¼and TEM showed a large number of autophagy vesicles containing swollen and deformed organelles in the AEC, and apparent reduction of intracellular mitochondria, these situations were obviously milder in both DEX and catgut embedding groups. Compared with the blank control group, the sneezing times, thickness of bronchial wall and bronchial smooth muscle in the model group were significantly increased (P<0.01), and the expressions of p-p38 MAPK and IL-4 in lung tissue were significantly increased (P<0.01), while the expression of IFN-γ was significantly decreased (P<0.01) in the model group. In comparison with the model group, the sneezing times, thickness of bronchial wall and bronchial smooth muscle, protein expressions of p-p38 MAPK and IL-4 were significantly decreased (P<0.01), while the expression of IFN-γ was obviously increased (P<0.01) in both the DEX and catgut embedding groups. CONCLUSIONS: Acupoint catgut embedding can reduce the expression of IL-4 and increase the expression of IFN-γ by inhibiting p38 MAPK signal pathway of lung tissues in BA rats, which may contribute to its effect in alleviating the degree of airway epithelial cells damage.
Asunto(s)
Asma , Interleucina-4 , Ratas , Masculino , Animales , Ratas Wistar , Interleucina-4/genética , Catgut , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Puntos de Acupuntura , Estornudo , Pulmón , Asma/genética , Asma/terapiaRESUMEN
Protein tyrosine phosphatases (PTPs) are an important class of enzymes that regulate protein tyrosine phosphorylation levels of a large variety of proteins in cells. Anomalies in protein tyrosine phosphorylation have been associated with the development of numerous human diseases, leading to a heightened interest in PTPs as promising targets for drug development. However, therapeutic targeting of PTPs has faced skepticism about their druggability. Besides the conventional small molecule inhibitors, proteolysis-targeting chimera (PROTAC) technology offers an alternative approach to target PTPs. PROTAC molecules utilize the ubiquitin-proteasome system to degrade specific proteins and have unique advantages compared with inhibitors: 1) PROTACs are highly efficient and can work at much lower concentrations than that expected based on their biophysical binding affinity; 2) PROTACs may achieve higher selectivity for the targeted protein than that dictated by their binding affinity alone; and 3) PROTACs may engage any region of the target protein in addition to the functional site. This review focuses on the latest advancement in the development of targeted PTP degraders and deliberates on the obstacles and prospective paths of harnessing this technology for therapeutic targeting of the PTPs.
Asunto(s)
Inhibidores Enzimáticos , Proteínas Tirosina Fosfatasas , Humanos , Proteolisis , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Estudios Prospectivos , Proteínas Tirosina Fosfatasas/metabolismo , Proteínas/metabolismo , Tirosina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.
Asunto(s)
Leucemia Mieloide Aguda , Monoéster Fosfórico Hidrolasas , Animales , Ratones , Leucemia Mieloide Aguda/genética , Mutación , Monoéster Fosfórico Hidrolasas/genética , Fosforilación , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Transducción de Señal/genéticaRESUMEN
The phosphatases of regenerating liver (PRL) are oncogenic when overexpressed. We previously found that PRL2 deletion increases PTEN, decreases Akt activity, and suppresses tumor development in a partial Pten-deficient mouse model. The current study aims to further establish the mechanism of PTEN regulation by PRL2 and expand the therapeutic potential for PTEN augmentation mediated by PRL2 inhibition in cancers initiated without PTEN alteration. The TP53 gene is the most mutated tumor suppressor in human cancers, and heterozygous or complete deletion of Tp53 in mice leads to the development of sarcomas and thymic lymphomas, respectively. There remains a lack of adequate therapies for the treatment of cancers driven by Tp53 deficiency or mutations. We show that Prl2 deletion leads to PTEN elevation and attenuation of Akt signaling in sarcomas and lymphomas developed in Tp53 deficiency mouse models. This results in increased survival and reduced tumor incidence because of impaired tumor cell proliferation. In addition, inhibition of PRL2 with a small-molecule inhibitor phenocopies the effect of genetic deletion of Prl2 and reduces Tp53 deficiency-induced tumor growth. Taken together, the results further establish PRL2 as a negative regulator of PTEN and highlight the potential of PRL2 inhibition for PTEN augmentation therapy in cancers with wild-type PTEN expression. SIGNIFICANCE: Prl2 deletion attenuates Tp53 deficiency-induced tumor growth by increasing PTEN and reducing Akt activity. Targeting Tp53-null lymphoma with PRL inhibitors lead to reduced tumor burden, providing a therapeutic approach via PTEN augmentation.
Asunto(s)
Linfoma , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Genes Supresores de Tumor , Linfoma/tratamiento farmacológico , Fosfohidrolasa PTEN/genéticaRESUMEN
Fluorinated liquid crystal monomers (FLCMs) have been suggested as emerging contaminants, raising global concern due to their frequent occurrence, potential toxic effects, and endurance capacity in the environment. However, the environmental fate of the FLCMs remains unknown. To fill this knowledge gap, we investigated the aerobic microbial transformation mechanisms of an important FLCM, 4-[difluoro(3,4,5-trifluorophenoxy)methyl]-3, 5-difluoro-4'-propylbiphenyl (DTMDPB), using an enrichment culture termed as BG1. Our findings revealed that 67.5 ± 2.1% of the initially added DTMDPB was transformed in 10 days under optimal conditions. A total of 14 microbial transformation products obtained due to a series of reactions (e.g., reductive defluorination, ether bond cleavage, demethylation, oxidative hydroxylation and aromatic ring opening, sulfonation, glucuronidation, O-methylation, and thiolation) were identified. Consortium BG1 harbored essential genes that could transform DTMDPB, such as dehalogenation-related genes [e.g., glutathione S-transferase gene (GST), 2-haloacid dehalogenase gene (2-HAD), nrdB, nuoC, and nuoD]; hydroxylating-related genes hcaC, ubiH, and COQ7; aromatic ring opening-related genes ligB and catE; and methyltransferase genes ubiE and ubiG. Two DTMDPB-degrading strains were isolated, which are affiliated with the genus Sphingopyxis and Agromyces. This study provides a novel insight into the microbial transformation of FLCMs. The findings of this study have important implications for the development of bioremediation strategies aimed at addressing sites contaminated with FLCMs.
Asunto(s)
Cristales Líquidos , Biodegradación Ambiental , HidroxilaciónRESUMEN
Covalent inhibition has gained increasing interest in targeting the undruggable protein tyrosine phosphatases (PTPs). However, a systematic method for discovering and characterizing covalent PTP inhibitors has yet to be established. Here, we describe a workflow involving high-throughput screening of covalent fragment libraries and a novel biochemical assay that enables the acquisition of kinetics parameters of PTP inhibition by covalent inhibitors with higher throughput.
Asunto(s)
Bioensayo , Ensayos Analíticos de Alto Rendimiento , Cinética , Física , Proteínas Tirosina FosfatasasRESUMEN
Contemporary strategies in cancer immunotherapy, despite remarkable success, remain constrained by inherent limitations such as suboptimal patient responses, the emergence of drug resistance, and the manifestation of pronounced adverse effects. Consequently, the need for alternative strategies for immunotherapy becomes clear. Protein tyrosine phosphatases (PTPs) wield a pivotal regulatory influence over an array of essential cellular processes. Substantial research has underscored the potential in targeting PTPs to modulate the immune responses and/or regulate antigen presentation, thereby presenting a novel paradigm for cancer immunotherapy. In this review, we focus on recent advances in genetic and biological validation of several PTPs as emerging targets for immunotherapy. We also highlight recent development of small molecule inhibitors and degraders targeting these PTPs as novel cancer immunotherapeutic agents.