BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare guidelines and modalities of patient consultation worldwide. The frequent cycles of quarantine confinement in Chile have caused mobility restrictions for patients and physicians, forcing the Hospital Las Higueras de Talcahuano (HHT) to replace the assisted televisit modality with a more classic televisit program. Here we have described if this change in televisit modality and type of outpatient may have impacted patients' satisfaction. METHODS: The patient's perception of satisfaction was evaluated through self-administered survey questionnaires previously validated in Spanish. Cohorts were grouped according to the following two relational models: (i) assisted televisit, 503 neurology patients from 2018 to 2019, and (ii) televisit, 831 patients from different specialties treated during 2020. Perception of satisfaction was compared by gender, age, and type of televisit, and internal consistency (Cronbach alpha) and reliability (factorial analysis of principal components) were assessed. Finally, we compared the patient satisfaction of both modalities. RESULTS: Questionnaires showed excellent internal consistency; all items showed point biserial correlations greater than 0.30. Assisted televisit and televisit cohorts comprised 64.2% and 67.6% females, respectively, and patients under the age of 65 years were 62.2% and 75%, respectively. Assisted televisit patients showed very high 94.4% (n=475) and high 5.2% (n=26) satisfaction levels, while televisit patients showed very high 22.3% (n=185), high 63.9% (n=531), and moderate 13.1% (n=109) satisfaction levels; this difference was statistically significant at p<0.001. CONCLUSION: Lower perception of satisfaction due to the change in televisit relational modality underscores the importance of primary care professionals who support the specialist in the assisted televisit model. However, the televisit modality showed high patient satisfaction and suggested that this modality can be a plausible alternative according to each location's reality. The results of this study indicate that both assisted televisit and televisit contribute to delivering an integrative solution that helps to alleviate the system's fragmentation.
ABSTRACT Introduction: Extracorporeal membrane oxygenation (ECMO) is the first-line therapy for temporary mechanical circulatory support allowing cardiac and pulmonary recovery or as a bridge to further therapeutic alternatives. The aim of this study was to report clinical outcomes in adult patients with refractory cardiac failure after open-heart surgery undergoing ECMO in a single center with an ECMO unit in Chile. Methods: We retrospectively analyzed adults with refractory cardiac failure after open-heart surgery who required a venoarterial (VA) ECMO between 2016 and 2021. Results: Of 16 patients with VA ECMO, 60% were men (n=10), 90% had hypertension (n=14), 69% had < 30% of left ventricular ejection fraction (n=11), and the mean European System for Cardiac Operative Risk Evaluation II score was 12 ± 11%. ECMO support with central cannulation accounts for 81% (n=13), and an intra-aortic balloon pump was used in nine patients (56%). The mean time of support was 4.7 ± 2.6 days (1.5 - 12 days). ECMO weaning was achieved in 88% of patients, and in-hospital mortality was 44% (n=7) after discharge. The freedom from all-cause mortality at one year of follow-up of the entire cohort was 38% (n=6). Conclusion: VA ECMO is now a well-known life-saving therapeutic option, but mortality and morbidity remain high. Implementation of an ECMO program with educational training is mandatory in order to find the proper balance between patient benefits, ethical considerations, and public health financial input in South America.
INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is the first-line therapy for temporary mechanical circulatory support allowing cardiac and pulmonary recovery or as a bridge to further therapeutic alternatives. The aim of this study was to report clinical outcomes in adult patients with refractory cardiac failure after open-heart surgery undergoing ECMO in a single center with an ECMO unit in Chile. METHODS: We retrospectively analyzed adults with refractory cardiac failure after open-heart surgery who required a venoarterial (VA) ECMO between 2016 and 2021. RESULTS: Of 16 patients with VA ECMO, 60% were men (n=10), 90% had hypertension (n=14), 69% had < 30% of left ventricular ejection fraction (n=11), and the mean European System for Cardiac Operative Risk Evaluation II score was 12 ± 11%. ECMO support with central cannulation accounts for 81% (n=13), and an intra-aortic balloon pump was used in nine patients (56%). The mean time of support was 4.7 ± 2.6 days (1.5 - 12 days). ECMO weaning was achieved in 88% of patients, and in-hospital mortality was 44% (n=7) after discharge. The freedom from all-cause mortality at one year of follow-up of the entire cohort was 38% (n=6). CONCLUSION: VA ECMO is now a well-known life-saving therapeutic option, but mortality and morbidity remain high. Implementation of an ECMO program with educational training is mandatory in order to find the proper balance between patient benefits, ethical considerations, and public health financial input in South America.
Cardiac Surgical Procedures , Extracorporeal Membrane Oxygenation , Heart Failure , Adult , Male , Humans , Female , Shock, Cardiogenic/etiology , Shock, Cardiogenic/surgery , Extracorporeal Membrane Oxygenation/adverse effects , Stroke Volume , Retrospective Studies , Ventricular Function, Left , Cardiac Surgical Procedures/adverse effects , Heart Failure/surgery , Heart Failure/complications
RESUMEN Introducción: En los pacientes críticos con COVID-19 ocurren una serie de alteraciones metabólicas, las cuales afectan directamente el estado nutricional del paciente. Para mejorar la sobrevida de los pacientes con COVID-19, se hace relevante el tratamiento nutricional oportuno, idealmente dentro de las primeras 24-48 horas de la admisión a la UCI. El objetivo de este estudio fue reportar la evolución, desde el ingreso hasta el egreso, del balance nitrogenado, diversos parámetros bioquímicos y el estado nutricional de los pacientes con neumonía por COVID-19. Método: Estudio observacional retrospectivo de temporalidad longitudinal, se realizó en la UCI del Hospital Las Higueras de Talcahuano, Chile. Se incluyeron a 33 pacientes al ingreso y al egreso de la UCI. Resultados: Se reportó un incremento significativo del balance nitrogenado al egreso de los pacientes de UCI, sin embargo, no se registraron cambios en la media de talla, peso, IMC, prevalencia de desnutrición durante la estancia en la UCI. La prevalencia de desnutrición moderada y severa fue de un 14,0%, valor inferior al 45,0% informado en pacientes con COVID-19. Conclusión: En este estudio se reportó que la implementación del protocolo y la terapia nutricionales durante la pandemia de COVID-19 se asoció a un aumento del balance nitrogenado y un mejor control glicémico en los pacientes que egresan de la UCI por neumonía de COVID-19.
ABSTRACT Introduction: In critically ill patients with COVID-19, a series of metabolic alterations occur, which directly affect the patient's nutritional status. To improve the survival of patients with COVID-19, timely nutritional treatment is relevant, ideally within the first 24-48 hours of admission to the ICU. The objective of this study was to report the evolution, from admission to discharge, of the nitrogen balance, various biochemical parameters and the nutritional status of patients with COVID-19 pneumonia. Method: We conducted a retrospective observational study in the ICU of Las Higueras Hospital in Talcahuano, Chile. Thirty-three patients were included at admission and discharge from the ICU. Results: A significant increase in nitrogen balance was reported at ICU patient discharge, however, no changes were recorded in mean height, weight, BMI, or prevalence of malnutrition during ICU stay. The prevalence of moderate and severe malnutrition was 14.0%, a value lower than the 45.0% reported in patients with COVID-19. Discussion: In this study we reported that the implementation of the nutritional protocol and therapy during the COVID-19 pandemic was associated with an increase in nitrogen balance and better glycemic control in patients discharged from the ICU due to COVID-19 pneumonia.
Oxidative stress produces macromolecules dysfunction and cellular damage. Renal ischemia-reperfusion injury (IRI) induces oxidative stress, inflammation, epithelium and endothelium damage, and cessation of renal function. The IRI is an inevitable process during kidney transplantation. Preliminary studies suggest that aminoguanidine (AG) is an antioxidant compound. In this study, we investigated the antioxidant effects of AG (50 mg/kg, intraperitoneal) and its association with molecular pathways activated by IRI (30 min/48 h) in the kidney. The antioxidant effect of AG was studied measuring GSSH/GSSG ratio, GST activity, lipoperoxidation, iNOS, and Hsp27 levels. In addition, we examined the effect of AG on elements associated with cell survival, inflammation, endothelium, and mesenchymal transition during IRI. AG prevented lipid peroxidation, increased GSH levels, and recovered the GST activity impaired by IRI. AG was associated with inhibition of iNOS, Hsp27, endothelial activation (VE-cadherin, PECAM), mesenchymal markers (vimentin, fascin, and HSP47), and inflammation (IL-1ß, IL-6, Foxp3, and IL-10) upregulation. In addition, AG reduced kidney injury (NGAL, clusterin, Arg-2, and TFG-ß1) and improved kidney function (glomerular filtration rate) during IRI. In conclusion, we found new evidence of the antioxidant properties of AG as a renoprotective compound during IRI. Therefore, AG is a promising compound to treat the deleterious effect of renal IRI.
BACKGROUND/AIMS: Renal ischemia and reperfusion injury (IRI) involves oxidative stress, disruption of microvasculature due to endothelial cell damage, loss of epithelial cell polarity secondary to cytoskeletal alterations, inflammation, and the subsequent transition into a mesenchymal phenotype. Ischemic preconditioning (IPC) has been proposed as a therapeutic strategy to avoid/ameliorate the IRI. Since previous results showed that IPC could have differential effects in kidney cortex vs. kidney medulla, in the present study we analyzed the effectiveness and molecular mechanisms implicated in IPC in both kidney regions. METHODS: We evaluated 3 experimental groups of BALB/c male mice: control (sham surgery); renal ischemia (30 min) by bilateral occlusion of the renal pedicle and reperfusion (48 hours) (I/R); and renal IPC (two cycles of 5 min of ischemia and 5 min of reperfusion) applied just before I/R. Acute kidney injury was evaluated by glomerular filtration rate (GFR), Neutrophil Gelatinase-Associated Lipocalin (NGAL) blood level, and histologic analysis. Oxidative stress was studied measurement the Glutathione S-Transferase (GST) activity, GSH/GSSG ratio, and lipoperoxidation levels. Inflammatory mediators (IL-1ß, IL-6, Foxp3, and IL-10) were quantified by qRT-PCR. The endothelial (PECAM-1), epithelial (AQP-1), mesenchymal (Vimentin, Fascin, and Hsp47), iNOS, clusterin, and Hsp27 expression were evaluated (qRT-PCR and/or Western blot). RESULTS: The IPC protocol prevented the decrease of GFR, reduced the plasma NGAL, and ameliorated morphological damage in the kidney cortex after I/R. The IPC also prevented the downregulation of GST activity, lipoperoxidation and ameliorated the oxidized glutathione. In addition, IPC prevented the upregulation of vimentin, fascin, and Hsp47, which was associated with the prevention of the downregulation of AQP1 after I/R. The protective effect of IPC was associated with the upregulation of Hsp27, Foxp3, and IL-10 expression in the renal cortex. However, the upregulation of iNOS, IL-1ß, IL-6, and clusterin by I/R were not modified by IPC. CONCLUSION: IPC conferred better protection in the kidney cortex as compared to the kidney medulla. The protective effect of IPC was associated with amelioration of oxidative stress, tubular damage, and the induction of markers of Treg lymphocytes activity in the cortical region. Further studies are needed to evaluate if lower tubular cell stress/damage after I/R may explain the preferential induction of Treg response in the kidney cortex induced by IPC.
Acute Kidney Injury/metabolism , Clusterin/metabolism , Glutathione Transferase/metabolism , Reperfusion Injury/metabolism , Acute Kidney Injury/prevention & control , Animals , Ischemic Preconditioning , Male , Mice, Inbred BALB C , Oxidative Stress , Reperfusion Injury/prevention & control
Background: Chile has a shortage of medical experts, including neurologists. The remote neurology program at Las Higueras Hospital in Talcahuano (HHT) was implemented in 2015 to decrease the number of patients waiting for their first appointment. Methods: This retrospective study analyzed a cohort of 2,904 ambulatory patients evaluated in the teleneurology program at the HHT between 2015 and 2019 who were referred from 16 primary and 3 tertiary healthcare centers. Results: Out of the 2,904 patients included in the study, 1,020 patients (35%) were male, and 1,884 (65%) were female. In total, 1,346 (46.0%) patients were under 60 years old (408 male and 938 female), and 1,558 (54%) were over 60 years old (612 male and 946 female). The patients were referred to a neurologist in the teleneurology program from different primary healthcare centers (93.5%) and tertiary healthcare centers (6.5%). The most common diseases diagnosed through teleneurology were, in decreasing order, headache (29.4%), Alzheimer's disease and other dementias (15.9%), and epilepsy (11.4%). From July 2018, we analyzed the patients' destination after the first teleneurology consultation. In the cohort of 634 patients who had their first consultation via the teleneurology program, 547 (86.3%) were instructed to continue follow-up via telemedicine. Conclusions: Data from this study show, for the first time in Chile, the significant contribution of the teleneurology program at the HHT to the diagnosis of a broad range of diseases in a substantial number of patients referred from primary and tertiary healthcare centers.
Backround There is a shortage of medical specialists in Chile, including neurologists; currently, there are 56,614 patients waiting for a first adult Neurology appointment in the country. The Teleneurology Program at the Hospital Las Higueras de Talcahuano (HHT) was implemented in 2015 to help reduce both the number of patients waiting for a first consultation and their waiting times. METHODS: This retrospective study analyzed a cohort of 8269 patients referred to the HHT Neurology clinic between 2013 and 2018, from primary, secondary, and tertiary health centers. Cox regression analyses were performed to determine the factors influencing each outcome (number of patients waiting for a consultation and waiting time), such as age, gender, referral health establishment and the type of consultation (whether in situ at the HHT or by synchronic telepresence through the Teleneurology Program). RESULTS: Out of the 8269 patients included in the study, 1743 consulted the neurologist through the Teleneurology Program, while 6526 received a consultation in situ at the HHT. Since its implementation (2015) until the end of 2018, the Teleneurology program contributed to decrease the number of patients waiting for their first appointment from 3084 to 298. Waiting time for the first consultation was 60% shorter for patients enrolled in the Teleneurology program than those with consultation in situ at HHT (6.23 ± 6.82 and 10.47 ± 8.70 months, respectively). Similar differences were observed when sorting patient data according to the referral health center. Cox regression analysis showed that patients waiting for a traditional in situ first adult Neurology consultation at the HHT had a higher risk (OR = 6.74) of waiting 90% longer than patients enrolled in the Teleneurology Program, without significant differences due to gender or age. CONCLUSIONS: Data from this study show a significant contribution of the Teleneurology Program at the HHT to decrease the number of patients waiting for a first consultation with a neurologist, as well as shorter waiting times, when derived from primary and secondary health centers.
Nervous System Diseases , Neurology , Referral and Consultation , Remote Consultation , Telemedicine , Waiting Lists , Adult , Chile , Cohort Studies , Female , Humans , Male , Middle Aged , Retrospective Studies
OBJECTIVE: Telemedicine arises as an attractive intervention for reducing the waiting time for appointments with medical specialists in Chile. Successful implementation of this technology requires safeguarding the patient/clinician trust relationship; however, no studies have been conducted to evaluate quality perception of a telemedicine program in Chile. To assess patient satisfaction with the Teleneurology program at the Hospital Higueras Talcahuano (HHT), addressing patient/clinician trust relationship. RESULTS: A perception survey was constructed with 23 questions, distributed into 5 key areas (items) of user satisfaction. Its face validity was performed by five neurology specialists from the Teleneurology unit of HHT. The survey was applied to 167 patients of the HHT, recruited between 2018 and 2019, for conducting a pilot cross-sectional descriptive study to assess internal consistency (Cronbach alpha) and reliability (factorial analysis of main components). The survey showed an internal consistency of 0.88. Removing any of the items maintained its reliability in values over 0.8. All items showed point biserial correlations greater than 0.30. Overall, the survey constructed and evaluated in this study showed high internal consistency and reliability values, which will allow its application in further studies of quality assessment of the Teleneurology unit of HHT.
Neurology/statistics & numerical data , Patient Satisfaction , Surveys and Questionnaires , Telemedicine/statistics & numerical data , Chile , Female , Humans , Male , Reproducibility of Results
On renal ischemia-reperfusion (I/R) injury, recruitment of neutrophils during the inflammatory process promotes local generation of oxygen and nitrogen reactive species, which, in turn, are likely to exacerbate tissue damage. The mechanism by which inducible nitric oxide synthase (iNOS) is involved in I/R has not been elucidated. In this work, the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine (l-NIL) and the NOS substrate l-arginine were employed to understand the role of NOS activity on the expression of particular target genes and the oxidative stress elicited after a 30-min of bilateral renal ischemia, followed by 48-h reperfusion in Balb/c mice. The main findings of the present study were that pharmacological inhibition of iNOS with l-NIL during an I/R challenge of mice kidney decreased renal injury, prevented tissue loss of integrity, and improved renal function. Several novel findings regarding the molecular mechanism by which iNOS inhibition led to these protective effects are as follows: 1) a prevention of the I/R-related increase in expression of Toll-like receptor 4 (TLR-4), and its downstream target, IL-1ß; 2) reduced oxidative stress following the I/R challenge; noteworthy, this study shows the first evidence of glutathione S-transferase (GST) inactivation following kidney I/R, a phenomenon fully prevented by iNOS inhibition; 3) increased expression of clusterin, a survival autophagy component; and 4) increased expression of nuclear factor of activated T cells 5 (NFAT-5) and its target gene aquaporin-1. In conclusion, prevention of renal damage following I/R by the pharmacological inhibition of iNOS with l-NIL was associated with the inactivation of proinflammatory pathway triggered by TLR-4, oxidative stress, renoprotection (autophagy inactivation), and NFAT-5 signaling pathway.
Clusterin/metabolism , Enzyme Inhibitors/therapeutic use , Glutathione Transferase/metabolism , Lysine/analogs & derivatives , Reperfusion Injury/prevention & control , Toll-Like Receptor 4/metabolism , Transcription Factors/metabolism , Acute Kidney Injury/prevention & control , Animals , Autophagy , Glomerular Filtration Rate , Lysine/therapeutic use , Male , Mice , Mice, Inbred BALB C , Nitric Oxide Synthase Type II/antagonists & inhibitors , Oxidative Stress/drug effects
OBJECTIVE: This study investigated the role of oxidative damage and nitric oxide (NO) synthases in the fetal heart using a model of intrauterine growth restriction induced by uteroplacental circulation restriction (UCR). METHODS: New Zealand white rabbits kept under 12-h light cycles, with food and water provided ad libitum, were subjected at day 25 of pregnancy to 40-50% uteroplacental artery ligation. We analyzed the gene expression of enzymes linked to nitric oxide synthesis (iNOS, eNOS, HO-1, and ARG-2), hypoxia inducible factor 1 alpha (HIF-1α), and the state of oxidative stress (protein carbonyl levels) in fetal heart homogenates. Additionally, we studied the histological morphology of the fetal heart. RESULTS: We found that fetal growth restriction was associated with a significant reduction in heart weight but a normal heart/body weight ratio in UCR animals. Hematoxylin and eosin staining showed normal left and right ventricular thickness but increased vessel dilatation with hyperemia in the hearts of the UCR group. We observed HIF-1α, eNOS, p-eNOS, and iNOS induction concomitant with intensified protein carbonyl levels but observed no changes in HO-1 or ARG-2 expression, suggesting increased NO and oxidative stress in the hearts of UCR animals. CONCLUSION: Uteroplacental circulation restriction increased NO-linked enzymes, oxidative damage, and dilated coronary vessels in fetal hearts. © 2017 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.
Fetal Growth Retardation , Fetal Heart/metabolism , Fetal Heart/pathology , Nitric Oxide Synthase/genetics , Oxidative Stress/physiology , Placental Circulation , Animals , Constriction, Pathologic/genetics , Constriction, Pathologic/metabolism , Constriction, Pathologic/pathology , Coronary Stenosis/genetics , Coronary Stenosis/metabolism , Coronary Stenosis/pathology , Enzyme Induction , Female , Fetal Growth Retardation/genetics , Fetal Growth Retardation/pathology , Gene Expression Regulation, Developmental , Pregnancy , Rabbits
OBJECTIVE: This work aimed to study the effect of uteroplacental circulation restriction on endothelial kidney damage in a fetal rabbit model. METHODS: New Zealand rabbits were subjected to 40% to 50% of uteroplacental artery ligation at day 25 of pregnancy. After 5 days, surviving fetuses were harvested by cesarean section. The gene and protein expressions of selected enzymes associated with nitric oxide production and oxidative stress were analyzed in fetal kidney homogenates. RESULTS: The placenta weight (6.06 ± 0.27, p < 0.0319) and fetal body (19.90 ± 1.03, p < 0.0001) were significantly reduced in the uteroplacental circulation restriction group. The kidneys from restricted fetuses presented a mild vascular congestion and glomerular capillary congestion, without inflammation or hypertrophy. We found endothelial nitric oxide synthase phosphorylation inhibition (0.23 ± 0.13, p < 0.012) and arginase-2 (0.29 ± 0.14, p < 0.023) protein induction in fetal kidneys of the circulation restriction group. Finally, the kidneys from circulation-restricted fetuses showed increased inducible nitric oxide synthase messenger RNA (mRNA) (2.68 ± 0.24, p < 0.01) and reduced heme oxygenase-1 mRNA (23 ± 1.3, p < 0.003), with increased reactive oxygen species (1.69 ± 0.09, p < 0.001) and nitrotyrosine protein (1.74 ± 0.28, p < 0.003) levels, without changes in Nox mRNA. CONCLUSION: We describe significant deregulation of vascular activity and oxidative damage in kidneys of fetal rabbits that have been exposed to restriction of the uterine circulation. © 2016 John Wiley & Sons, Ltd.
Arginase/metabolism , Fetal Growth Retardation/genetics , Heme Oxygenase-1/genetics , Kidney Glomerulus/metabolism , Nitric Oxide Synthase/genetics , Oxidative Stress/genetics , Animals , Disease Models, Animal , Female , Fetal Growth Retardation/metabolism , Heme Oxygenase-1/metabolism , Kidney/metabolism , Kidney/pathology , Kidney Glomerulus/pathology , Nitric Oxide/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide Synthase Type III/metabolism , Phosphorylation , Placental Circulation , Pregnancy , RNA, Messenger/metabolism , Rabbits , Reactive Oxygen Species/metabolism , Transcriptome , Tyrosine/analogs & derivatives , Tyrosine/metabolism
The evolutionarily conserved Notch signal transduction pathway regulates fundamental cellular processes during embryonic development and in the adult. Ligand binding induces presenilin-dependent cleavage of the receptor and a subsequent nuclear translocation of the Notch intracellular domain (NICD). In the nucleus, NICD binds to the recombination signal sequence-binding protein J (RBP-J)/CBF-1 transcription factor to induce expression of Notch target genes. Here, we report the identification and functional characterization of RBP-J interacting and tubulin associated (RITA) (C12ORF52) as a novel RBP-J/CBF-1-interacting protein. RITA is a highly conserved 36 kDa protein that, most interestingly, binds to tubulin in the cytoplasm and shuttles rapidly between cytoplasm and nucleus. This shuttling RITA exports RBP-J/CBF-1 from the nucleus. Functionally, we show that RITA can reverse a Notch-induced loss of primary neurogenesis in Xenopus laevis. Furthermore, RITA is able to downregulate Notch-mediated transcription. Thus, we propose that RITA acts as a negative modulator of the Notch signalling pathway, controlling the level of nuclear RBP-J/CBF-1, where its amounts are limiting.
Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Microtubule-Associated Proteins/metabolism , Receptors, Notch/metabolism , Xenopus Proteins/metabolism , Xenopus laevis/metabolism , Active Transport, Cell Nucleus , Animals , Centrosome/ultrastructure , Cytoplasm/metabolism , Cytoplasm/ultrastructure , Gene Expression , HeLa Cells , Humans , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , Microtubule-Associated Proteins/analysis , Microtubule-Associated Proteins/genetics , Neurogenesis , Protein Binding , Protein Transport , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Receptors, Notch/genetics , Transcription, Genetic , Tubulin/metabolism , Xenopus Proteins/analysis , Xenopus Proteins/genetics , Xenopus laevis/genetics
Timely acquisition of cell fates and the elaborate control of growth in numerous organs depend on Notch signaling. Upon ligand binding, the core transcription factor RBP-J activates transcription of Notch target genes. In the absence of signaling, RBP-J switches off target gene expression, assuring the tight spatiotemporal control of the response by a mechanism incompletely understood. Here we show that the histone demethylase KDM5A is an integral, conserved component of Notch/RBP-J gene silencing. Methylation of histone H3 Lys 4 is dynamically erased and re-established at RBP-J sites upon inhibition and reactivation of Notch signaling. KDM5A interacts physically with RBP-J; this interaction is conserved in Drosophila and is crucial for Notch-induced growth and tumorigenesis responses.
Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Receptors, Notch/metabolism , Retinoblastoma-Binding Protein 2/metabolism , Signal Transduction , Animals , Cell Line , Cell Line, Tumor , DNA-Binding Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila melanogaster , Histones/metabolism , Humans , Jumonji Domain-Containing Histone Demethylases , Mice , T-Lymphocytes , Ubiquitin-Protein Ligases
