RESUMEN
Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.
Asunto(s)
Relojes Circadianos , Neoplasias Pancreáticas , Animales , Ratones , Humanos , Relojes Circadianos/genética , Ritmo Circadiano/genética , Minociclina , Neoplasias Pancreáticas/genética , Factores de Transcripción ARNTL/genética , Factores de Transcripción ARNTL/metabolismo , Neoplasias PancreáticasRESUMEN
Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in ILC22 cells that resulted in less secretion of IL-22 and inadequate protection against intestinal bacterial infection. Ahr(-/-) mice also lacked postnatally 'imprinted' cryptopatches and isolated lymphoid follicles (ILFs), but not embryonically 'imprinted' Peyer's patches. AHR induced the transcription factor Notch, which was required for NKp46(+) ILCs, whereas LTi-like ILCs, cryptopatches and ILFs were partially dependent on Notch signaling. Thus, AHR was essential for ILC22 cells and postnatal intestinal lymphoid tissues. Moreover, ILC22 subsets were heterogeneous in their requirement for Notch and their effect on the generation of intestinal lymphoid tissues.
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Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Antígenos Ly/metabolismo , Femenino , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/metabolismo , Interleucinas/genética , Interleucinas/inmunología , Interleucinas/metabolismo , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Transducción de Señal/inmunología , Interleucina-22RESUMEN
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that is a member of the PER-ARNT-SIM superfamily of environmental sensors. This receptor has been a molecule of interest for many years in the field of toxicology, as it was originally discovered to mediate the toxic effects of certain environmental pollutants like benzo(a)pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin. While all animals express this protein, there is naturally occurring variability in receptor size and responsiveness to ligand. This naturally occurring variation, particularly in mice, has been an essential tool in the discovery and early characterization of the AHR. Genetic models including congenic mice and induced mutations at the Ahr locus have proven invaluable in further understanding the role of the AHR in adaptive metabolism and TCDD-induced toxicity. The creation and examination of Ahr null mice revealed an important physiological role for the AHR in vascular and hepatic development and mediation of the immune system. In this review, we attempt to provide an overview to many of the AHR models that have aided in the understanding of AHR biology thus far. We describe the naturally occurring polymorphisms, congenic models, induced mutations at the Ahr locus and at the binding partner Ah Receptor Nuclear Translocator and chaperone, Ah receptor associated 9 loci in mice, with a brief description of naturally occurring and induced mutations in rats.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo , Dibenzodioxinas Policloradas , Receptores de Hidrocarburo de Aril , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Humanos , Ratones , Modelos Animales , Ratas , Receptores de Hidrocarburo de Aril/genéticaRESUMEN
The Ah receptor (AHR) has been studied for almost five decades. Yet, we still have many important questions about its role in normal physiology and development. Moreover, we still do not fully understand how this protein mediates the adverse effects of a variety of environmental pollutants, such as the polycyclic aromatic hydrocarbons (PAHs), the chlorinated dibenzo-p-dioxins ("dioxins"), and many polyhalogenated biphenyls. To provide a platform for future research, we provide the historical underpinnings of our current state of knowledge about AHR signal transduction, identify a few areas of needed research, and then develop concepts such as adaptive metabolism, ligand structural diversity, and the importance of proligands in receptor activation. We finish with a discussion of the cognate physiological role of the AHR, our perspective on why this receptor is so highly conserved, and how we might think about its cognate ligands in the future.
Asunto(s)
Contaminantes Ambientales/farmacología , Dibenzodioxinas Policloradas/farmacología , Hidrocarburos Policíclicos Aromáticos/farmacología , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Contaminantes Ambientales/química , Humanos , Ligandos , Estructura Molecular , Dibenzodioxinas Policloradas/química , Hidrocarburos Policíclicos Aromáticos/química , Receptores de Hidrocarburo de Aril/genética , Transducción de Señal/efectos de los fármacosRESUMEN
The aryl hydrocarbon receptor (AHR) belongs to the PAS (PER-ARNT-SIM) family transcription factors and mediates broad responses to numerous environmental pollutants and cellular metabolites, modulating diverse biological processes from adaptive metabolism, acute toxicity, to normal physiology of vascular and immune systems. The AHR forms a transcriptionally active heterodimer with ARNT (AHR nuclear translocator), which recognizes the dioxin response element (DRE) in the promoter of downstream genes. We determined the crystal structure of the mammalian AHR-ARNT heterodimer in complex with the DRE, in which ARNT curls around AHR into a highly intertwined asymmetric architecture, with extensive heterodimerization interfaces and AHR interdomain interactions. Specific recognition of the DRE is determined locally by the DNA-binding residues, which discriminates it from the closely related hypoxia response element (HRE), and is globally affected by the dimerization interfaces and interdomain interactions. Changes at the interdomain interactions caused either AHR constitutive nuclear localization or failure to translocate to nucleus, underlying an allosteric structural pathway for mediating ligand-induced exposure of nuclear localization signal. These observations, together with the global higher flexibility of the AHR PAS-A and its loosely packed structural elements, suggest a dynamic structural hierarchy for complex scenarios of AHR activation induced by its diverse ligands.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Dimerización , Regulación de la Expresión Génica , Humanos , Ratones , Estructura Cuaternaria de ProteínaRESUMEN
Cellular metabolites act as important signaling cues, but are subject to complex unknown chemistry. Kynurenine is a tryptophan metabolite that plays a crucial role in cancer and the immune system. Despite its atypical, non-ligand-like, highly polar structure, kynurenine activates the aryl hydrocarbon receptor (AHR), a PER, ARNT, SIM (PAS) family transcription factor that responds to diverse environmental and cellular ligands. The activity of kynurenine is increased 100-1000-fold by incubation or long-term storage and relies on the hydrophobic ligand-binding pocket of AHR, with identical structural signatures for AHR induction before and after activation. We purified trace-active derivatives of kynurenine and identified two novel, closely related condensation products, named trace-extended aromatic condensation products (TEACOPs), which are active at low picomolar levels. The synthesized compound for one of the predicted structures matched the purified compound in both chemical structure and AHR pharmacology. Our study provides evidence that kynurenine acts as an AHR pro-ligand, which requires novel chemical conversions to act as a receptor agonist.
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Quinurenina/química , Quinurenina/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Sitios de Unión , Cinética , Ligandos , Ratones , Estructura Molecular , Receptores de Hidrocarburo de Aril/química , Receptores de Hidrocarburo de Aril/genéticaRESUMEN
BACKGROUND: Autoimmune diseases have increased in incidence and prevalence worldwide. While genetic predispositions play a role, environmental factors are a major contributor. Atmospheric particulate matter (PM) is a complex mixture composed of metals, nitrates, sulfates and diverse adsorbed organic compounds like polycyclic aromatic hydrocarbons (PAHs) and dioxins. Exposure to atmospheric PM aggravates autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, among others. PAHs and dioxins are known aryl hydrocarbon receptor (AHR) ligands. The AHR modulates T cell differentiation and directs the balance between effector and regulatory T cells in vitro and in experimental autoimmune encephalomyelitis (EAE), a murine model of autoimmune disease. This study aims to identify pathways that contribute to autoimmune disease and their potential use as therapeutic targets to alleviate symptoms and the need for global immunosuppression. This study tests the hypothesis that atmospheric PM enhances effector T cell differentiation and aggravates autoimmune disease. RESULTS: An atmospheric ambient urban dust PM sample, standard reference material (SRM)1649b, was tested for its effects on autoimmunity. SRM1649b PM enhanced Th17 differentiation in an AHR-dependent manner in vitro, however intranasal treatment of SRM1649b PM delayed onset of EAE and reduced cumulative and peak clinical scores. Chronic and acute intranasal exposure of SRM1649b PM delayed onset of EAE. Chronic intranasal exposure did not reduce severity of EAE while acute intranasal exposure significantly reduced severity of disease. Acute intranasal treatment of low dose SRM1649b PM had no effect on clinical score or day of onset in EAE. Delayed onset of EAE by intranasal SRM1649b PM was AHR-dependent in vivo. Oral gavage of SRM1649b PM, in the absence of AHR ligands in the diet, had no effect on day of disease onset or severity of EAE. Day 10 analysis of T cells in the CNS after intranasal treatment of SRM1649b PM showed a reduction of pathologic T cell subsets in vivo. Moreover, MOG-specific splenocytes require AHR to generate or maintain IL-10 producing cells and reduce IFNγ producing cells in vitro. CONCLUSIONS: These results identify the AHR pathway as a potential target for driving targeted immunosuppression in the CNS in the context of atmospheric PM-mediated autoimmune disease. The effects of SRM1649b PM on EAE are dependent on route of exposure, with intranasal treatment reducing severity of EAE and delaying disease onset while oral gavage has no effect. Intranasal SRM1649b PM reduces pathologic T cells in the CNS, specifically Th1 cells and Th1Th17 double positive cells, leading to reduced severity of EAE and AHR-dependent delayed disease onset. Additionally, SRM1649b PM treatment of antigen-specific T cells leads to AHR-dependent increase in percent IL-10 positive cells in vitro. These findings may shed light on the known increase of infection after exposure to atmospheric PM and serve as the first step in identifying components of the AHR pathway responsible for Th1-mediated immunosuppression in response to atmospheric PM exposure.
Asunto(s)
Contaminantes Atmosféricos/toxicidad , Material Particulado/toxicidad , Animales , Polvo , Encefalomielitis Autoinmune Experimental , Ratones , Ratones Endogámicos C57BL , Receptores de Hidrocarburo de Aril , Células Th17RESUMEN
The Toll-like receptor 7 agonist imiquimod (IMQ) is an approved drug for the topical treatment of various skin diseases that, in addition, is currently tested in multiple clinical trials for the immunotherapy of various types of cancers. As all of these trials include application of IMQ to the skin and evidence exists that exposure to environmental pollutants, i.e., tobacco smoke, affects its therapeutic efficacy, the current study aims to elucidate the cutaneous metabolism of the drug. Treatment of human keratinocytes with 2.5 µM benzo[a]pyrene (BaP), a tobacco smoke constituent and aryl hydrocarbon receptor (AHR) agonist, for 24 h induced cytochrome P450 (CYP) 1A enzyme activity. The addition of IMQ 30 min prior measurement resulted in a dose-dependent inhibition of CYP1A activity, indicating that IMQ is either a substrate or inhibitor of CYP1A isoforms. Incubation of 21 recombinant human CYP enzymes with 0.5 µM IMQ and subsequent LC-MS analyses, in fact, identified CYP1A1 and CYP1A2 as being predominantly responsible for IMQ metabolism. Accordingly, treatment of keratinocytes with BaP accelerated IMQ clearance and the associated formation of monohydroxylated IMQ metabolites. A co-incubation with 5 µM 7-hydroxyflavone, a potent inhibitor of human CYP1A isoforms, abolished basal as well as BaP-induced IMQ metabolism. Further studies with hepatic microsomes from CD-1 as well as solvent- and ß-naphthoflavone-treated CYP1A1/CYP1A2 double knock-out and respective control mice confirmed the critical contribution of CYP1A isoforms to IMQ metabolism. Hence, an exposure to life style-related, dietary, and environmental AHR ligands may affect the pharmacokinetics and, thus, treatment efficacy of IMQ.
Asunto(s)
Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Imiquimod/metabolismo , Queratinocitos/metabolismo , Adulto , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Células Cultivadas , Cromatografía Liquida , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A2/genética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imiquimod/administración & dosificación , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microsomas Hepáticos/metabolismo , Persona de Mediana Edad , Receptores de Hidrocarburo de Aril/metabolismoRESUMEN
BACKGROUND: Exposure to particulate matter (PM) has been associated with increased incidence and severity of autoimmune disease. Diesel PM is primarily composed of an elemental carbon core and adsorbed organic compounds such as polycyclic aromatic hydrocarbons (PAHs) and contributes up to 40% of atmospheric PM. The organic fraction (OF) of PM excludes all metals and inorganics and retains most organic compounds, such as PAHs. Both PM and OF increase inflammation in vitro and aggravate autoimmune disease in humans. PAHs are known aryl hydrocarbon receptor (AHR) ligands. The AHR modulates T cell differentiation and effector function in vitro and in experimental autoimmune encephalomyelitis (EAE), a murine model of autoimmune disease. This study aims to identify whether the total mass or active components of PM are responsible for activating pathways associated with exposure to PM and autoimmune disease. This study tests the hypothesis that active components present in diesel PM and their OF enhance effector T cell differentiation and aggravate autoimmune disease. RESULTS: Two different diesel samples, each characterized for their components, were tested for their effects on autoimmunity. Both diesel PM enhanced effector T cell differentiation in an AHR-dose-dependent manner and suppressed regulatory T cell differentiation in vitro. Both diesel PM aggravated EAE in vivo. Fractionated diesel OFs exhibited the same effects as PM in vitro, but unlike PM, only one diesel OF aggravated EAE. Additionally, both synthetic PAH mixtures that represent specific PAHs found in the two diesel PM samples enhanced Th17 differentiation, however one lost this effect after metabolism and only one required the AHR. CONCLUSIONS: These findings suggest that active components of PM and not total mass are driving T cell responses in vitro, but in vivo the PM matrix and complex mixtures adsorbed to the particles, not just the OF, are contributing to the observed EAE effects. This implies that examining OF alone may not be sufficient in vivo. These data further suggest that bioavailability and metabolism of organics, especially PAHs, may have an important role in vivo.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Encefalomielitis Autoinmune Experimental/inducido químicamente , Material Particulado/toxicidad , Hidrocarburos Policíclicos Aromáticos/toxicidad , Emisiones de Vehículos/toxicidad , Animales , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Material Particulado/química , Hidrocarburos Policíclicos Aromáticos/químicaRESUMEN
The circadian clock plays a significant role in many aspects of female reproductive biology, including estrous cycling, ovulation, embryonic implantation, onset of puberty, and parturition. In an effort to link cell-specific circadian clocks to their specific roles in female reproduction, we used the promoter that controls expression of Steroidogenic Factor-1 (SF1) to drive Cre-recombinase-mediated deletion of the brain muscle arnt-like 1 (Bmal1) gene, known to encode an essential component of the circadian clock (SF1-Bmal1(-/-)). The resultant SF1-Bmal1(-/-) females display embryonic implantation failure, which is rescued by progesterone supplementation, or bilateral or unilateral transplantation of wild-type ovaries into SF1-Bmal1(-/-) dams. The observation that the central clock, and many other peripheral clocks, are fully functional in this model allows the assignment of the implantation phenotype to the clock in ovarian steroidogenic cells and distinguishes it from more general circadian related systemic pathology (e.g., early onset arthropathy, premature aging, ovulation, late onset of puberty, and abnormal estrous cycle). Our ovarian transcriptome analysis reveals that deletion of ovarian Bmal1 disrupts expression of transcripts associated with the circadian machinery and also genes critical for regulation of progesterone production, such as steroidogenic acute regulatory factor (Star). Overall, these data provide a powerful model to probe the interlocking and synergistic network of the circadian clock and reproductive systems.
Asunto(s)
Factores de Transcripción ARNTL/deficiencia , Factores de Transcripción ARNTL/fisiología , Implantación del Embrión/fisiología , Ovario/citología , Ovario/fisiología , Esteroides/biosíntesis , Factores de Transcripción ARNTL/genética , Envejecimiento/genética , Envejecimiento/fisiología , Animales , Ritmo Circadiano/genética , Ritmo Circadiano/fisiología , Implantación del Embrión/efectos de los fármacos , Implantación del Embrión/genética , Estro/genética , Estro/fisiología , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovario/trasplante , Embarazo , Progesterona/administración & dosificación , Regiones Promotoras Genéticas , Maduración Sexual/genética , Maduración Sexual/fisiología , Factor Esteroidogénico 1/genéticaRESUMEN
The diurnal variation in acetaminophen (APAP) hepatotoxicity (chronotoxicity) reportedly is driven by oscillations in metabolism that are influenced by the circadian phases of feeding and fasting. To determine the relative contributions of the central clock and the hepatocyte circadian clock in modulating the chronotoxicity of APAP, we used a conditional null allele of brain and muscle Arnt-like 1 (Bmal1, aka Mop3 or Arntl) allowing deletion of the clock from hepatocytes while keeping the central and other peripheral clocks (e.g., the clocks controlling food intake) intact. We show that deletion of the hepatocyte clock dramatically reduces APAP bioactivation and toxicity in vivo and in vitro because of a reduction in NADPH-cytochrome P450 oxidoreductase gene expression, protein, and activity.
Asunto(s)
Acetaminofén/farmacocinética , Analgésicos no Narcóticos/farmacocinética , Ritmo Circadiano , Sistema Enzimático del Citocromo P-450/biosíntesis , Regulación del Desarrollo de la Expresión Génica , Hepatocitos/enzimología , Acetaminofén/efectos adversos , Acetaminofén/farmacología , Analgésicos no Narcóticos/efectos adversos , Analgésicos no Narcóticos/farmacología , Animales , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Péptidos y Proteínas de Señalización del Ritmo Circadiano/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Hepatocitos/patología , Ratones , Ratones TransgénicosRESUMEN
OBJECTIVE: To determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis. BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We investigated the involvement of AHR, a ligand-activated transcriptional regulator, in colitis-associated colorectal tumorigenesis. METHODS: We used a mouse model of colitis-associated colorectal tumorigenesis that employs treatment with azoxymethane and dextran sodium sulfate. We examined the role of AHR using both an Ahr-deletion mouse model (Ahr) and treatment with the AHR pro-agonist indole-3-carbinol (I3C). Incidence, multiplicity, and location of tumors were visually counted. Tumors were defined as neoplasms. Intestinal inflammation was assessed by quantitative PCR for proinflammatory markers and colon length. Data were evaluated and compared using GraphPad Prism software (version 6, La Jolla, CA). RESULTS: Tumor incidence was increased 32% in Ahr null mice and tumor multiplicity was approximately increased 3-fold compared with wild-type mice (2.4 vs 7; P < 0.05). Furthermore, tumor multiplicity was reduced 92% by treatment of I3C in wild-type mice, whereas the suppressor effect of I3C was not observed in Ahr null mice (P < 0.05). CONCLUSIONS: We found that AHR plays a protective role in colitis-associated colorectal tumorigenesis. This conclusion is based on the observations that Ahr null mice showed increased number of colorectal tumors, and mice treated with I3C exhibited fewer tumors. This study supports the use of AHR agonists such as I3C as a chemopreventive therapy for IBD-associated CRC in human patients.
Asunto(s)
Colitis/complicaciones , Neoplasias Colorrectales/prevención & control , Receptores de Hidrocarburo de Aril/fisiología , Animales , Azoximetano/farmacología , Daño del ADN , Sulfato de Dextran , Expresión Génica , Indoles/farmacología , Indoles/uso terapéutico , Ratones , Ratones Endogámicos C57BL , ARN/análisis , Receptores de Hidrocarburo de Aril/agonistasAsunto(s)
Dibenzofuranos/toxicidad , Dioxinas/toxicidad , Sondas Moleculares/toxicidad , Animales , Dibenzofuranos/historia , Dibenzofuranos/metabolismo , Dioxinas/historia , Dioxinas/metabolismo , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Sondas Moleculares/historia , Sondas Moleculares/metabolismoRESUMEN
The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock and Bmal1 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective beta-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the beta-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
Asunto(s)
Factores de Transcripción ARNTL/genética , Proteínas CLOCK/genética , Ritmo Circadiano/fisiología , Diabetes Mellitus/metabolismo , Insulina/sangre , Islotes Pancreáticos/metabolismo , Factores de Transcripción ARNTL/deficiencia , Factores de Transcripción ARNTL/metabolismo , Envejecimiento/genética , Envejecimiento/patología , Animales , Glucemia/análisis , Glucemia/metabolismo , Proteínas CLOCK/deficiencia , Proteínas CLOCK/metabolismo , Proliferación Celular , Tamaño de la Célula , Supervivencia Celular , Ritmo Circadiano/genética , Diabetes Mellitus/genética , Perfilación de la Expresión Génica , Intolerancia a la Glucosa/genética , Prueba de Tolerancia a la Glucosa , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/patología , Ratones , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fenotipo , Sueño/genética , Sueño/fisiología , Vesículas Sinápticas/metabolismo , Vigilia/genética , Vigilia/fisiologíaRESUMEN
The Per-Arnt-Sim (PAS) domain is conserved across the kingdoms of life and found in an ever-growing list of proteins. This domain can bind to and sense endogenous or xenobiotic small molecules such as molecular oxygen, cellular metabolites, or polyaromatic hydrocarbons. Members of this family are often found in pathways that regulate responses to environmental change; in mammals these include the hypoxia, circadian, and dioxin response pathways. These pathways function in development and throughout life to regulate cellular, organ, and whole-organism adaptive responses. Remarkably, in the case of the clock, this adaptation includes anticipation of environmental change. In this review, we summarize the roles of PAS domain-containing proteins in mammals. We provide structural evidence that functionally classifies both known and unknown biological roles. Finally, we discuss the role of PAS proteins in anticipation of and adaptation to environmental change.
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Adaptación Fisiológica/fisiología , Translocador Nuclear del Receptor de Aril Hidrocarburo/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología , Ambiente , Proteínas Circadianas Period/fisiología , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/genética , Secuencia de Aminoácidos , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/química , Translocador Nuclear del Receptor de Aril Hidrocarburo/clasificación , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/química , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/clasificación , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Ritmo Circadiano/fisiología , Dioxinas/toxicidad , Humanos , Hipoxia/patología , Mamíferos/fisiología , Proteínas Circadianas Period/química , Proteínas Circadianas Period/clasificación , Proteínas Circadianas Period/genética , Hidrocarburos Policíclicos Aromáticos/toxicidad , Transducción de Señal/efectos de los fármacos , Terminología como AsuntoRESUMEN
The PAS (PER, ARNT, SIM) protein family plays a vital role in mammalian biology and human disease. This analysis arose from an interest in the signaling mechanics by the Ah receptor (AHR) and the Ah receptor nuclear translocator (ARNT). After more than fifty years by studying this and related mammalian sensor systems, describing the role of PAS domains in signal transduction is still challenging. In this perspective, we attempt to interpret recent studies of mammalian PAS protein structure and consider how this new insight might explain how these domains are employed in human signal transduction with an eye towards developing strategies to target and engineer these molecules for a new generation of therapeutics. Our approach is to integrate our understanding of PAS protein history, cell biology, and molecular biology with recent structural discoveries to help explain the mechanics of mammalian PAS protein signaling. As a learning set, we focus on sequences and crystal structures of mammalian PAS protein dimers that can be visualized using readily available software.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo , Receptores de Hidrocarburo de Aril , Animales , Humanos , Translocador Nuclear del Receptor de Aril Hidrocarburo/química , Receptores de Hidrocarburo de Aril/química , Multimerización de ProteínaRESUMEN
A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.
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Proteínas CLOCK , Ritmo Circadiano , Diabetes Mellitus Tipo 2 , Humanos , Animales , Ritmo Circadiano/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Obesidad/genética , Obesidad/metabolismo , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Relojes Circadianos/genéticaRESUMEN
OBJECTIVES: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear. To address this gap, we evaluated the role of AHR in the development of PDAC precancerous lesions in vivo . MATERIALS AND METHODS: We created a global AHR-null, mutant Kras -driven PDAC mouse model (A -/- KC) and evaluated the changes in PDAC precursor lesion formation (PanIN-1, 2, and 3) and associated fibro-inflammation between KC and A -/- KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. RESULTS: We identified a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A -/- KC versus KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. CONCLUSIONS: These findings show the loss of AHR results in heightened Kras -induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.
Asunto(s)
Modelos Animales de Enfermedad , Ratones Noqueados , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Receptores de Hidrocarburo de Aril , Microambiente Tumoral , Animales , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Microambiente Tumoral/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Mutación , Ratones , Ratones Endogámicos C57BL , Inflamación/genéticaRESUMEN
The human gut microbiome, the host, and the environment are inextricably linked across the life course with significant health impacts. Consisting of trillions of bacteria, fungi, viruses, and other micro-organisms, microbiota living within our gut are particularly dynamic and responsible for digestion and metabolism of diverse classes of ingested chemical pollutants. Exposure to chemical pollutants not only in early life but throughout growth and into adulthood can alter human hosts' ability to absorb and metabolize xenobiotics, nutrients, and other components critical to health and longevity. Inflammation is a common mechanism underlying multiple environmentally related chronic conditions, including cardiovascular disease, multiple cancer types, and mental health. While growing research supports complex interactions between pollutants and the gut microbiome, significant gaps exist. Few reviews provide descriptions of the complex mechanisms by which chemical pollutants interact with the host microbiome through either direct or indirect pathways to alter disease risk, with a particular focus on inflammatory pathways. This review focuses on examples of several classes of pollutants commonly ingested by humans, including (i) heavy metals, (ii) persistent organic pollutants (POPs), and (iii) nitrates. Digestive enzymes and gut microbes are the first line of absorption and metabolism of these chemicals, and gut microbes have been shown to alter compounds from a less to more toxic state influencing subsequent distribution and excretion. In addition, chemical pollutants may interact with or alter the selection of more harmful and less commensal microbiota, leading to gut dysbiosis, and changes in receptor-mediated signaling pathways that alter the integrity and function of the gut intestinal tract. Arsenic, cadmium, and lead (heavy metals), influence the microbiome directly by altering different classes of bacteria, and subsequently driving inflammation through metabolite production and different signaling pathways (LPS/TLR4 or proteoglycan/TLR2 pathways). POPs can alter gut microbial composition either directly or indirectly depending on their ability to activate key signaling pathways within the intestine (e.g., PCB-126 and AHR). Nitrates and nitrites' effect on the gut and host may depend on their ability to be transformed to secondary and tertiary metabolites by gut bacteria. Future research should continue to support foundational research both in vitro, in vivo, and longitudinal population-based research to better identify opportunities for prevention, gain additional mechanistic insights into the complex interactions between environmental pollutants and the microbiome and support additional translational science.
RESUMEN
Human familial isolated pituitary adenoma (FIPA) has been linked to germline heterozygous mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP, also known as ARA9, XAP2, FKBP16, or FKBP37). To investigate the hypothesis that AIP is a pituitary adenoma tumor suppressor via its role in aryl hydrocarbon receptor (AHR) signaling, we have compared the pituitary phenotype of our global null Aip (AipΔC) mouse model with that of a conditional null Aip model (Aipfx/fx) carrying the same deletion, as well as pituitary phenotypes of Ahr global null and Arnt conditional null animals. We demonstrate that germline AipΔC heterozygosity results in a high incidence of pituitary tumors in both sexes, primarily somatotropinomas, at 16 months of age. Biallelic deletion of Aip in Pit-1 cells (Aipfx/fx:rGHRHRcre) increased pituitary tumor incidence and also accelerated tumor progression, supporting a loss-of-function/loss-of-heterozygosity model of tumorigenesis. Tumor development exhibited sexual dimorphism in wildtype and Aipfx/fx:rGHRHRcre animals. Despite the role of AHR as a tumor suppressor in other cancers, the observation that animals lacking AHR in all tissues, or ARNT in Pit-1 cells, do not develop somatotropinomas argues against the hypothesis that pituitary tumorigenesis in AIP-associated FIPA is related to decreased activities of either the Ahr or Arnt gene products.