RESUMEN
AMP-activated protein kinase (AMPK) is a master sensor and regulator of cellular energy status. Upon metabolic stress, AMPK suppresses anabolic and promotes catabolic processes to regain energy homeostasis. Cancer cells can occasionally suppress the growth-restrictive AMPK pathway by mutation of an upstream regulatory kinase. Here, we describe a widespread mechanism to suppress AMPK through its ubiquitination and degradation by the cancer-specific MAGE-A3/6-TRIM28 ubiquitin ligase. MAGE-A3 and MAGE-A6 are highly similar proteins normally expressed only in the male germline but frequently re-activated in human cancers. MAGE-A3/6 are necessary for cancer cell viability and are sufficient to drive tumorigenic properties of non-cancerous cells. Screening for targets of MAGE-A3/6-TRIM28 revealed that it ubiquitinates and degrades AMPKα1. This leads to inhibition of autophagy, activation of mTOR signaling, and hypersensitization to AMPK agonists, such as metformin. These findings elucidate a germline mechanism commonly hijacked in cancer to suppress AMPK.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Metabolismo Energético , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Alineación de Secuencia , Transducción de Señal , Testículo/metabolismoRESUMEN
Nutrient-responsive protein kinases control the balance between anabolic growth and catabolic processes such as autophagy. Aberrant regulation of these kinases is a major cause of human disease. We report here that the vertebrate nonreceptor tyrosine kinase Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristylation sites (SRMS) inhibits autophagy and promotes growth in a nutrient-responsive manner. Under nutrient-replete conditions, SRMS phosphorylates the PHLPP scaffold FK506-binding protein 51 (FKBP51), disrupts the FKBP51-PHLPP complex, and promotes FKBP51 degradation through the ubiquitin-proteasome pathway. This prevents PHLPP-mediated dephosphorylation of AKT, causing sustained AKT activation that promotes growth and inhibits autophagy. SRMS is amplified and overexpressed in human cancers where it drives unrestrained AKT signaling in a kinase-dependent manner. SRMS kinase inhibition activates autophagy, inhibits cancer growth, and can be accomplished using the FDA-approved tyrosine kinase inhibitor ibrutinib. This illuminates SRMS as a targetable vulnerability in human cancers and as a new target for pharmacological induction of autophagy in vertebrates.
Asunto(s)
Autofagia , Neoplasias/metabolismo , Neoplasias/patología , Proteínas de Unión a Tacrolimus/metabolismo , Familia-src Quinasas/metabolismo , Adenina/análogos & derivados , Adenina/farmacología , Animales , Autofagia/efectos de los fármacos , Beclina-1/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Ratones , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatasas/metabolismo , Fosforilación/efectos de los fármacos , Fosfotirosina/metabolismo , Piperidinas/farmacología , Unión Proteica/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
Natural products continue to provide a platform to study biological systems. A bioguided study of cancer cell models led us to a new member of the jatrophane natural products from Jatropha gossypiifolia, which was independently identified and characterized as jatrogossone A (1). Purification and structure elucidation was performed by column chromatography and high-performance liquid chromatography-mass spectrometry and NMR techniques, and the structure was confirmed via X-ray crystallography. The unique molecular scaffold of jatrogossone A prompted an evaluation of its mode of action. Cytotoxicity assays demonstrated that jatrogossone A displays selective antiproliferative activity against cancer cell models in the low micromolar range with a therapeutic window. Jatrogossone A (1) affects mitochondrial membrane potential (ΔΨm) in a time- and dose-dependent manner. This natural product induces radical oxygen species (ROS) selectively in cancer cellular models, with minimal ROS induction in noncancerous cells. Compound 1 induces ROS in the mitochondria, as determined by colocalization studies, and it induces mitophagy. It promotes also in vitro cell death by causing cell arrest at the G2/M stage, caspase (3/7) activation, and PARP-1 cleavage. The combined findings provide a potential mechanism by which 1 relies on upregulation of mitochondrial ROS to potentiate cytotoxic effects through intracellular signaling.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Acetilcisteína/farmacología , Antineoplásicos Fitogénicos/química , Antioxidantes/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Jatropha/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitofagia/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/metabolismoRESUMEN
Modern cancer treatment employs many effective chemotherapeutic agents originally discovered from natural sources. The cyclic depsipeptide didemnin B has demonstrated impressive anticancer activity in preclinical models. Clinical use has been approved but is limited by sparse patient responses combined with toxicity risk and an unclear mechanism of action. From a broad-scale effort to match antineoplastic natural products to their cellular activities, we found that didemnin B selectively induces rapid and wholesale apoptosis through dual inhibition of PPT1 and EEF1A1. Furthermore, empirical discovery of a small panel of exceptional responders to didemnin B allowed the generation of a regularized regression model to extract a sparse-feature genetic biomarker capable of predicting sensitivity to didemnin B. This may facilitate patient selection in a fashion that could enhance and expand the therapeutic application of didemnin B against neoplastic disease.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Depsipéptidos/farmacología , Proteínas de la Membrana/antagonistas & inhibidores , Factor 1 de Elongación Peptídica/antagonistas & inhibidores , Farmacogenética , Apoptosis/genética , Biomarcadores/metabolismo , Línea Celular Tumoral , Estudio de Asociación del Genoma Completo , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina , Proteínas de la Membrana/genética , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Factor 1 de Elongación Peptídica/genética , Biosíntesis de Proteínas/efectos de los fármacos , Biosíntesis de Proteínas/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Tioléster Hidrolasas , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genéticaRESUMEN
Chemicals found in nature have evolved over geological time scales to productively interact with biological molecules, and thus represent an effective resource for pharmaceutical development. Marine-derived bacteria are rich sources of chemically diverse, bioactive secondary metabolites, but harnessing this diversity for biomedical benefit is limited by challenges associated with natural product purification and determination of biochemical mechanism. Using Functional Signature Ontology (FUSION), we report the parallel isolation and characterization of a marine-derived natural product, N6,N6-dimethyladenosine, that robustly inhibits AKT signaling in a variety of non-small cell lung cancer cell lines. Upon validation of the elucidated structure by comparison with a commercially available sample, experiments were initiated to understand the small molecule's breadth of effect in a biological setting. One such experiment, a reverse phase protein array (RPPA) analysis of >50 kinases, indicated a specific cellular response to treatment. In all, leveraging the FUSION platform allowed for the rapid generation and validation of a biological mechanism of action hypothesis for an unknown natural product and permitted accelerated purification of the bioactive component from a chemically complex fraction.
Asunto(s)
Organismos Acuáticos/química , Bacterias/química , Productos Biológicos/química , Productos Biológicos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Ontologías Biológicas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
The MAP3K (Mitogen Activated Protein Kinase Kinase Kinase) TAOK2 (Thousand-And-One Kinase 2) is an activator of p38 MAP kinase cascade that is up-regulated in response to environmental stresses. A synthetic lethal screen performed using a NSCLC (non-small cell lung cancer) cell line, and a second screen identifying potential modulators of autophagy have implicated TAOK2 as a potential cancer therapeutic target. Using a 200,000 compound high throughput screen, we identified three specific small molecule compounds that inhibit the kinase activity of TAOK2. These compounds also showed inhibition of autophagy. Based on SAR (structure-activity relationship) studies, we have predicted the modifications on the reactive groups for the three compounds.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/química , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/toxicidad , Relación Estructura-Actividad , Temperatura de Transición , Proteínas Quinasas p38 Activadas por Mitógenos/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation, and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A-D (1-4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1-4, determined by detailed two-dimensional (2D) NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[d]pyrrolo][1,3]oxazine-3,5-dione core. Discoipyrroles A-D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show selective cytotoxicity to DDR2 mutant lung cancer cell lines (IC50 120-400 nM). Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a nonenzymatic process, leading to a one-pot total synthesis of 1.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Bacillus/química , Productos Biológicos/farmacología , Fibroblastos/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Pirrolidinonas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Receptores Mitogénicos/antagonistas & inhibidores , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Receptores con Dominio Discoidina , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/citología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/aislamiento & purificación , Humanos , Modelos Moleculares , Estructura Molecular , Pirrolidinonas/química , Pirrolidinonas/aislamiento & purificación , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Mitogénicos/genética , Receptores Mitogénicos/metabolismo , Transducción de Señal/efectos de los fármacos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In this issue of Cell Chemical Biology, You et al. demonstrate that selective degradation of ERK5 exhibits neither anti-proliferative nor anti-inflammatory activities previously attributed to ERK5 inactivation. This settles a longstanding debate in the field and highlights the power of PROTACs to investigate non-enzymatic activities of target proteins.
Asunto(s)
Proteínas , Proteolisis , Proteínas/metabolismoRESUMEN
Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. The FA proteins have functions in genome maintenance and in the cytoplasmic process of selective autophagy, beyond their canonical roles of repairing DNA interstrand cross-links. FA core complex proteins FANCC, FANCF, FANCL, FANCA, FANCD2, BRCA1 and BRCA2, which previously had no known direct functions outside the nucleus, have recently been implicated in mitophagy. Although mutations in FANCL account for only a very small number of cases in FA families, it plays a key role in the FA pathophysiology and might drive carcinogenesis. Here, we demonstrate that FANCL protein is present in mitochondria in the control and Oligomycin and Antimycin (OA)-treated cells and its ubiquitin ligase activity is not required for its localization to mitochondria. CRISPR/Cas9-mediated knockout of FANCL in HeLa cells overexpressing parkin results in increased sensitivity to mitochondrial stress and defective clearing of damaged mitochondria upon OA treatment. This defect was reversed by the reintroduction of either wild-type FANCL or FANCL(C307A), a mutant lacking ubiquitin ligase activity. To summarize, FANCL protects from mitochondrial stress and supports Parkin-mediated mitophagy in a ubiquitin ligase-independent manner.
Asunto(s)
Anemia de Fanconi , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Proteína del Grupo de Complementación L de la Anemia de Fanconi , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Células HeLa , Humanos , Mitofagia , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Mutations that aberrantly activate trithorax-group proteins, Hox transcription factors and TALE-class Hox cofactors promote leukemogenesis, but their target genes critical for leukemogenesis remain largely unknown. Through genetic analyses in C. elegans, we find that the trithorax-group gene lin-59 and the TALE-class Hox cofactor unc-62 are required for survival of the VC motor neurons. With the goal of providing a model for how aberrantly active Hox complexes might promote leukemia, we elucidate the mechanism through which these new inhibitors of programmed cell death act: lin-59 maintains transcription of the Hox gene lin-39, while unc-62 promotes nuclear localization of the TALE-class Hox cofactor ceh-20. A LIN-39/CEH-20 complex binds the promoter of the pro-apoptotic BH3-only gene egl-1, repressing its transcription and ensuring survival of the VC neurons. In the absence of this regulatory mechanism, egl-1 is transcribed and the VC neurons die. Furthermore, ectopic expression of the Hox gene lin-39, as occurs for human Hox genes in leukemia, is sufficient to block death of some cells. This work identifies BH3-only pro-apoptotic genes as targets of Hox-mediated repression and suggests that aberrant activation of Hox networks may promote leukemia in part by inhibiting apoptosis.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Supervivencia Celular/fisiología , Proteínas de Homeodominio/fisiología , Proteínas Represoras/genética , Apoptosis/genética , Ensayo de Cambio de Movilidad Electroforética , Proteínas de Homeodominio/genética , Humanos , Neuronas Motoras/citología , Mutagénesis Sitio-Dirigida , Transcripción GenéticaRESUMEN
Overexpression studies have identified X-linked inhibitor of apoptosis protein (XIAP) as a potent inhibitor of caspases. However, the exact function of endogenous XIAP in regulating mammalian apoptosis is less clear. Endogenous XIAP strictly regulates cytochrome c-dependent caspase activation in sympathetic neurons but not in many mitotic cells. We report that postmitotic cardiomyocytes, unlike fibroblasts, are remarkably resistant to cytosolic microinjection of cytochrome c. The cardiomyocyte resistance to cytochrome c is mediated by endogenous XIAP, as XIAP-deficient cardiomyocytes die rapidly with cytosolic cytochrome c alone. Importantly, we found that cardiomyocytes, like neurons, have markedly reduced Apaf-1 levels and that this decrease in Apaf-1 is directly linked to the tight regulation of caspase activation by XIAP. These data identify an important function of XIAP in cardiomyocytes and point to a striking similarity in the regulation of apoptosis in postmitotic cells.
Asunto(s)
Apoptosis/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Animales , Factor Apoptótico 1 Activador de Proteasas , Caspasas/metabolismo , Células Cultivadas , Citocromos c/metabolismo , Citocromos c/farmacología , Citosol/metabolismo , Ratones , Microinyecciones , Microscopía Fluorescente , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Ratas , Factores de Tiempo , Transfección , Proteína Inhibidora de la Apoptosis Ligada a X/farmacologíaRESUMEN
Mitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.
RESUMEN
Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Leucemia/tratamiento farmacológico , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Caspasas/genética , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos/métodos , Inducción Enzimática/efectos de los fármacos , Compuestos Heterocíclicos/química , Humanos , Ratones , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Índice TerapéuticoRESUMEN
Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs). The predicted mechanism of actions span a broad spectrum of cellular mechanisms, many of which are not currently recognized as "druggable." To enable use of FuSiOn as a hypothesis generation resource, all associations and analyses are available within an open source web-based GUI (http://fusion.yuhs.ac).
Asunto(s)
Productos Biológicos/farmacología , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Programas Informáticos , Productos Biológicos/química , Células HCT116 , Células HeLa , Humanos , Fenotipo , Transcriptoma , Células Tumorales CultivadasRESUMEN
Bcr-Abl, activated in chronic myelogenous leukemias, is a potent cell death inhibitor. Previous reports have shown that Bcr-Abl prevents apoptosis through inhibition of mitochondrial cytochrome c release. We report here that Bcr-Abl also inhibits caspase activation after the release of cytochrome c. Bcr-Abl inhibited caspase activation by cytochrome c added to cell-free lysates and prevented apoptosis when cytochrome c was microinjected into intact cells. Bcr-Abl acted posttranslationally to prevent the cytochrome c-induced binding of Apaf-1 to procaspase 9. Although Bcr-Abl prevented interaction of endogenous Apaf-1 with the recombinant prodomain of caspase 9, it did not affect the association of endogenous caspase 9 with the isolated Apaf-1 caspase recruitment domain (CARD) or Apaf-1 lacking WD-40 repeats. These data suggest that Apaf-1 recruitment of caspase 9 is faulty in the presence of Bcr-Abl and that cytochrome c/dATP-induced exposure of the Apaf-1 CARD is likely defective. These data provide a novel locus of Bcr-Abl antiapoptotic action and suggest a distinct mechanism of apoptosomal inhibition.
Asunto(s)
Apoptosis , Citocromos c/metabolismo , Proteínas de Fusión bcr-abl/fisiología , Mitocondrias/metabolismo , Animales , Factor Apoptótico 1 Activador de Proteasas , Western Blotting , Caspasa 9 , Caspasas/metabolismo , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Citosol/metabolismo , Activación Enzimática , Fibroblastos/metabolismo , Glutatión/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Células HL-60 , Humanos , Inmunoprecipitación , Células K562 , Ratones , Fosfotirosina/química , Unión Proteica , Procesamiento Proteico-Postraduccional , Estructura Terciaria de Proteína , Proteínas/metabolismo , Ratas , Proteínas Recombinantes/metabolismo , Temperatura , Factores de Tiempo , XenopusRESUMEN
A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by small interfering RNA (siRNA) and synthetic microRNA (miRNA) libraries. With this strategy, we matched proteins and miRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected siRNAs, miRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets.
Asunto(s)
Productos Biológicos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Transcriptoma/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Autofagia/genética , Bacterias/química , Bacterias/clasificación , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Línea Celular Tumoral , Células Cultivadas , Análisis por Conglomerados , Biología Computacional/métodos , Evaluación Preclínica de Medicamentos/métodos , Redes Reguladoras de Genes/efectos de los fármacos , Redes Reguladoras de Genes/genética , Células HCT116 , Humanos , Invertebrados/química , Células MCF-7 , Biología Marina , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Estructura Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos , Interferencia de ARNRESUMEN
Cancer is a complex disease in which cells have circumvented normal restraints on tissue growth and have acquired complex abnormalities in their genomes, posing a considerable challenge to identifying the pathways and mechanisms that drive fundamental aspects of the malignant phenotype. Genetic analyses of the normal development of the nematode Caenorhabditis elegans have revealed evolutionarily conserved mechanisms through which individual cells establish their fates, and how they make and execute the decision to survive or undergo programmed cell death. The pathways identified through these studies have mammalian counterparts that are co-opted by malignant cells. Effective cancer drugs now target some of these pathways, and more are likely to be discovered.
Asunto(s)
Caenorhabditis elegans/fisiología , Muerte Celular , Linaje de la Célula , Animales , Investigación Biomédica , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animales de Enfermedad , Oncología MédicaRESUMEN
Hox genes are crucial determinants of cell fates and of body morphology of animals; mutations affecting these genes result in abnormal patterns of programmed cell death. How Hox genes regulate programmed cell death is an important and poorly understood aspect of normal development. In the nematode C. elegans, the Hox gene mab-5 is required for the programmed cell deaths of two lineally related cells generated in the P11 and P12 lineages. We show here that in the P11 lineage, a complex between MAB-5 and the Pbx homolog CEH-20 directly regulates transcription of the BH3 domain gene egl-1 to initiate programmed cell death; in the P12 lineage, mab-5 and ceh-20 apparently act indirectly to initiate programmed cell death. Direct regulation of programmed cell death may be an evolutionarily ancient and conserved function of Hox genes.