RESUMEN
Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology. The hypoxia-inducible factors (HIFs) are transcriptional activators that function as master regulators of oxygen homeostasis in all metazoan species. Rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of HIF dysregulation in chronic diseases, and investigating potential targeting of HIFs for therapeutic purposes.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Evolución Biológica , Oxígeno/metabolismo , Animales , Enfermedad Crónica , Desarrollo Embrionario , Humanos , Hipoxia/metabolismoRESUMEN
The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells.
Asunto(s)
Hipoxia de la Célula , Dioxigenasas/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias/metabolismo , Piruvato Quinasa/metabolismo , Animales , Línea Celular Tumoral , Dioxigenasas/genética , Retroalimentación , Técnicas de Silenciamiento del Gen , Técnicas de Inactivación de Genes , Células HeLa , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Redes y Vías Metabólicas , Ratones , Elementos de Respuesta , Activación Transcripcional , Factores de Transcripción p300-CBP/metabolismoRESUMEN
T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T(reg)) and T(H)17 differentiation. HIF-1 enhances T(H)17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating T(H)17 signature genes. Concurrently, HIF-1 attenuates T(reg) development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of T(H)17-dependent experimental autoimmune encephalitis associated with diminished T(H)17 and increased T(reg) cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Linfocitos T Reguladores/citología , Células Th17/citología , Animales , Secuencia de Bases , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Factores de Transcripción Forkhead/metabolismo , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Interleucina-17/genética , Interleucina-17/inmunología , Células Jurkat , Ratones , Datos de Secuencia Molecular , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Factor de Transcripción STAT3/metabolismo , Alineación de Secuencia , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Factores de Transcripción p300-CBP/metabolismoRESUMEN
Red blood cells transport O2 from the lungs to body tissues. Hypoxia stimulates kidney cells to secrete erythropoietin (EPO), which increases red cell mass. Hypoxia-inducible factors (HIFs) mediate EPO gene transcriptional activation. HIF-α subunits are subject to O2-dependent prolyl hydroxylation and then bound by the von Hippel-Lindau protein (VHL), which triggers their ubiquitination and proteasomal degradation. Mutations in the genes encoding EPO, EPO receptor, HIF-2α, prolyl hydroxylase domain protein 2 (PHD2), or VHL cause familial erythrocytosis. In addition to O2, α-ketoglutarate is a substrate for PHD2, and analogs of α-ketoglutarate inhibit hydroxylase activity. In phase III clinical trials evaluating the treatment of anemia in chronic kidney disease, HIF prolyl hydroxylase inhibitors were as efficacious as darbepoetin alfa in stimulating erythropoiesis. However, safety concerns have arisen that are focused on thromboembolism, which is also a phenotypic manifestation of VHL or HIF-2α mutation, suggesting that these events are on-target effects of HIF prolyl hydroxylase inhibitors.
Asunto(s)
Eritropoyesis , Inhibidores de Prolil-Hidroxilasa , Humanos , Eritropoyesis/genética , Inhibidores de Prolil-Hidroxilasa/farmacología , Inhibidores de Prolil-Hidroxilasa/uso terapéutico , Ácidos Cetoglutáricos , Hipoxia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
Aberrant activation of the hypoxia-inducible transcription factor HIF-1 and dysfunction of the tumor suppressor p53 have been reported to induce malignant phenotypes and therapy resistance of cancers. However, their mechanistic and functional relationship remains largely unknown. Here, we reveal a mechanism by which p53 deficiency triggers the activation of HIF-1-dependent hypoxia signaling and identify zinc finger and BTB domain-containing protein 2 (ZBTB2) as an important mediator. ZBTB2 forms homodimers via its N-terminus region and increases the transactivation activity of HIF-1 only when functional p53 is absent. The ZBTB2 homodimer facilitates invasion, distant metastasis, and growth of p53-deficient, but not p53-proficient, cancers. The intratumoral expression levels of ZBTB2 are associated with poor prognosis in lung cancer patients. ZBTB2 N-terminus-mimetic polypeptides competitively inhibit ZBTB2 homodimerization and significantly suppress the ZBTB2-HIF-1 axis, leading to antitumor effects. Our data reveal an important link between aberrant activation of hypoxia signaling and loss of a tumor suppressor and provide a rationale for targeting a key mediator, ZBTB2, to suppress cancer aggressiveness.
Asunto(s)
Neoplasias , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Hipoxia/genética , Unión Proteica , Transducción de Señal , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Hipoxia de la Célula/genética , Proteínas Represoras/genéticaRESUMEN
Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.
Asunto(s)
Neoplasias Óseas , Condrosarcoma , Encondromatosis , Enfermedades Vasculares , Humanos , Encondromatosis/complicaciones , Encondromatosis/genética , Encondromatosis/patología , Condrosarcoma/patología , Análisis de Secuencia de ADN , Subunidad alfa del Factor 1 Inducible por Hipoxia/genéticaRESUMEN
Cancers express a large battery of genes by which they establish an immunosuppressive tumor microenvironment. Many of these genes are induced by intratumoral hypoxia through transcriptional activation mediated by hypoxia-inducible factors HIF-1 and HIF-2. This review summarizes several recent reports describing hypoxia-induced mechanisms of immune evasion in sarcoma and breast, colorectal, hepatocellular, prostate and uterine cancer. These studies point to several novel therapeutic approaches to improve anti-tumor immunity and increase responses to immunotherapy.
Asunto(s)
Neoplasias , Masculino , Humanos , Neoplasias/genética , Neoplasias/terapia , Hipoxia/genética , Microambiente Tumoral/genéticaRESUMEN
Hypoxia-inducible factors (HIFs) were discovered as activators of erythropoietin gene transcription in response to reduced oxygen (O2) availability. O2-dependent hydroxylation of HIFs on proline and asparagine residues regulates protein stability and transcriptional activity, respectively. Mutations in genes encoding components of the O2-sensing pathway cause familial erythrocytosis. Several small-molecule inhibitors of HIF prolyl hydroxylases are currently in clinical trials as erythropoiesis-stimulating agents. HIFs are overexpressed in bone marrow neoplasms, and the development of HIF inhibitors may improve outcomes in these disorders.
Asunto(s)
Oxígeno , Policitemia , Hematopoyesis , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Prolina Dioxigenasas del Factor Inducible por Hipoxia/metabolismo , Oxígeno/metabolismo , Policitemia/genética , Policitemia/metabolismoRESUMEN
Calreticulin (CALR) is a multifunctional protein that participates in various cellular processes, which include calcium homeostasis, cell adhesion, protein folding, and cancer progression. However, the role of CALR in breast cancer (BC) is unclear. Here, we report that CALR is overexpressed in BC compared with normal tissue, and its expression is correlated with patient mortality and stemness indices. CALR expression was increased in mammosphere cultures, CD24-CD44+ cells, and aldehyde dehydrogenase-expressing cells, which are enriched for breast cancer stem cells (BCSCs). Additionally, CALR knockdown led to BCSC depletion, which impaired tumor initiation and metastasis and enhanced chemosensitivity in vivo. Chromatin immunoprecipitation and reporter assays revealed that hypoxia-inducible factor 1 (HIF-1) directly activated CALR transcription in hypoxic BC cells. CALR expression was correlated with Wnt/ß-catenin pathway activation, and an activator of Wnt/ß-catenin signaling abrogated the inhibitory effect of CALR knockdown on mammosphere formation. Taken together, our results demonstrate that CALR facilitates BC progression by promoting the BCSC phenotype through Wnt/ß-catenin signaling in an HIF-1-dependent manner and suggest that CALR may represent a target for BC therapy.
Asunto(s)
Calreticulina/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Células Madre Neoplásicas/metabolismo , Aldehído Deshidrogenasa/metabolismo , Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/fisiopatología , Carcinogénesis/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Progresión de la Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Factor 1 Inducible por Hipoxia/genética , Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Células Madre Neoplásicas/fisiología , Vía de Señalización Wnt/fisiología , beta Catenina/metabolismoRESUMEN
Breast cancer patients with increased expression of hypoxia-inducible factors (HIFs) in primary tumor biopsies are at increased risk of metastasis, which is the major cause of breast cancer-related mortality. The mechanisms by which intratumoral hypoxia and HIFs regulate metastasis are not fully elucidated. In this paper, we report that exposure of human breast cancer cells to hypoxia activates epidermal growth factor receptor (EGFR) signaling that is mediated by the HIF-dependent expression of a disintegrin and metalloprotease 12 (ADAM12), which mediates increased ectodomain shedding of heparin-binding EGF-like growth factor, an EGFR ligand, leading to EGFR-dependent phosphorylation of focal adhesion kinase. Inhibition of ADAM12 expression or activity decreased hypoxia-induced breast cancer cell migration and invasion in vitro, and dramatically impaired lung metastasis after orthotopic implantation of MDA-MB-231 human breast cancer cells into the mammary fat pad of immunodeficient mice.
Asunto(s)
Proteína ADAM12/genética , Proteína ADAM12/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica , Hipoxia/metabolismo , Proteína ADAM12/deficiencia , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular , Receptores ErbB/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Humanos , Pulmón/patología , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , Metástasis de la Neoplasia/genética , Transducción de Señal , Microambiente TumoralRESUMEN
Human survival is dependent upon the continuous delivery of O2 to each cell in the body in sufficient amounts to meet metabolic requirements, primarily for ATP generation by oxidative phosphorylation. Hypoxia-inducible factors (HIFs) regulate the transcription of thousands of genes to balance O2 supply and demand. The HIFs are negatively regulated by O2-dependent hydrox-ylation and ubiquitination by prolyl hydroxylase domain (PHD) proteins and the von Hippel-Lindau (VHL) protein. Germline mutations in the genes encoding VHL, HIF-2α, and PHD2 cause hereditary erythrocytosis, which is characterized by polycythemia and pulmonary hypertension and is caused by increased HIF activity. Evolutionary adaptation to life at high altitude is associated with unique genetic variants in the genes encoding HIF-2α and PHD2 that blunt the erythropoietic and pulmonary vascular responses to hypoxia.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Genómica/métodos , Mutación de Línea Germinal , Homeostasis , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Oxígeno/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , HumanosRESUMEN
The transcription factor HIF-1 mediates adaptive responses to hypoxia, and its activity is negatively regulated by O2-dependent binding of the von Hippel-Lindau (VHL) protein. In this issue, Boutin et al. (2008) use conditional knockout mice to demonstrate that sensing of O2 by keratinocytes in the epidermis leads to alterations in cutaneous blood flow that affect the production of the hormone erythropoietin, thereby modulating red blood cell production and the O2-carrying capacity of blood.
Asunto(s)
Oxígeno/metabolismo , Fenómenos Fisiológicos de la Piel , Animales , Humanos , Factor 1 Inducible por Hipoxia/metabolismo , Queratinocitos/metabolismo , RatonesRESUMEN
Activation of the innate and adaptive immune systems represents a promising strategy for defeating cancer. However, during tumor progression, cancer cells battle to shift the balance from immune activation to immunosuppression. Critical sites of this battle are regions of intratumoral hypoxia, and a major driving force for immunosuppression is the activity of hypoxia-inducible factors, which regulate the transcription of large batteries of genes in both cancer and stromal cells that block the infiltration and activity of cytotoxic T lymphocytes and natural killer cells, while stimulating the infiltration and activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. Targeting hypoxia-inducible factors or their target gene products may restore anticancer immunity and improve the response to immunotherapies.
Asunto(s)
Evasión Inmune , Neoplasias , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Humanos , HipoxiaRESUMEN
Hypoxia-inducible factors (HIFs) control transcriptional responses to reduced O2 availability. HIFs are heterodimeric proteins composed of an O2-regulated HIF-α subunit and a constitutively expressed HIF-1ß subunit. HIF-α subunits are subject to prolyl hydroxylation, which targets the proteins for degradation under normoxic conditions. Small molecule prolyl hydroxylase inhibitors, which stabilize the HIF-α subunits and increase HIF-dependent expression of erythropoietin, are in phase III clinical trials for the treatment of anemia in patients with chronic kidney disease. HIFs contribute to the pathogenesis of many cancers, particularly the clear cell type of renal cell carcinoma in which loss of function of the von Hippel-Lindau tumor suppressor blocks HIF-2α degradation. A small molecule inhibitor that binds to HIF-2α and blocks dimerization with HIF-1ß is in clinical trials for the treatment of renal cell carcinoma. Targeting HIFs for stabilization or inhibition may improve outcomes in diseases that are common causes of mortality in the US population.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Animales , Ensayos Clínicos Fase III como Asunto , Humanos , Neoplasias/metabolismoRESUMEN
Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer.
Asunto(s)
Factores de Transcripción Forkhead/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Células Cultivadas , Citocinas/metabolismo , Inhibidores Enzimáticos , Células HEK293 , Proteínas HSP70 de Choque Térmico/genética , Humanos , Imidazoles , Inflamación/genética , Inflamación/inmunología , Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos BALB C , Fenotipo , Piridinas , Interferencia de ARN , ARN Interferente Pequeño , Linfocitos T Colaboradores-Inductores/inmunología , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
The molecular mechanisms regulating sympathetic innervation of the heart during embryogenesis and its importance for cardiac development and function remain to be fully elucidated. We generated mice in which conditional knockout (CKO) of the Hif1a gene encoding the transcription factor hypoxia-inducible factor 1α (HIF-1α) is mediated by an Islet1-Cre transgene expressed in the cardiac outflow tract, right ventricle and atrium, pharyngeal mesoderm, peripheral neurons, and hindlimbs. These Hif1aCKO mice demonstrate significantly decreased perinatal survival and impaired left ventricular function. The absence of HIF-1α impaired the survival and proliferation of preganglionic and postganglionic neurons of the sympathetic system, respectively. These defects resulted in hypoplasia of the sympathetic ganglion chain and decreased sympathetic innervation of the Hif1aCKO heart, which was associated with decreased cardiac contractility. The number of chromaffin cells in the adrenal medulla was also decreased, indicating a broad dependence on HIF-1α for development of the sympathetic nervous system.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/fisiología , Sistema Nervioso Simpático/crecimiento & desarrollo , Médula Suprarrenal/embriología , Médula Suprarrenal/inervación , Animales , Células Cromafines , Anomalías de los Vasos Coronarios/embriología , Vasos Coronarios/embriología , Femenino , Ganglios Simpáticos/embriología , Ganglios Simpáticos/crecimiento & desarrollo , Corazón/embriología , Corazón/inervación , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Sistema Nervioso Simpático/enzimologíaRESUMEN
Reduced oxygen availability (hypoxia) leads to increased production of reactive oxygen species (ROS) by the electron transport chain. Here, I review recent work delineating mechanisms by which hypoxia-inducible factor 1 (HIF-1) mediates adaptive metabolic responses to hypoxia, including increased flux through the glycolytic pathway and decreased flux through the tricarboxylic acid cycle, in order to decrease mitochondrial ROS production. HIF-1 also mediates increased flux through the serine synthesis pathway and mitochondrial one-carbon (folate cycle) metabolism to increase mitochondrial antioxidant production (NADPH and glutathione). Dynamic maintenance of ROS homeostasis is required for induction of the breast cancer stem cell phenotype in response to hypoxia or cytotoxic chemotherapy. Consistently, inhibition of phosphoglycerate dehydrogenase, the first enzyme of the serine synthesis pathway, in breast cancer cells impairs tumor initiation, metastasis, and response to cytotoxic chemotherapy. I discuss how these findings have important implications for understanding the logic of the tumor microenvironment and for improving therapeutic responses in women with breast cancer.
Asunto(s)
Regulación de la Expresión Génica , Glucosa/metabolismo , Factor 1 Inducible por Hipoxia/metabolismo , Oxidación-Reducción , Células Madre/fisiología , Antioxidantes/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Redes y Vías Metabólicas , Especies Reactivas de Oxígeno/metabolismo , Células Madre/enzimologíaRESUMEN
Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O2 availability and play critical roles in development, physiology, and disease pathogenesis. Mutations that dysregulate HIF activity are the genetic basis for tumor predisposition in the von Hippel-Lindau syndrome and excess red blood cell production in hereditary erythrocytosis.
Asunto(s)
Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Predisposición Genética a la Enfermedad , Oxígeno/metabolismo , Fenotipo , Biomarcadores , Diagnóstico Diferencial , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Policitemia/congénito , Policitemia/diagnóstico , Policitemia/metabolismo , Transducción de Señal , Enfermedad de von Hippel-Lindau/diagnóstico , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/metabolismoRESUMEN
Hypoxia-inducible factors (HIFs) activate gene transcription in response to reduced O2 availability and play critical roles in development, physiology, and disease pathogenesis. Mutations that dysregulate HIF activity are the genetic basis for tumor predisposition in the von Hippel-Lindau syndrome and excess red blood cell production in hereditary erythrocytosis.