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PURPOSE: To evaluate the long-term anatomic and visual outcomes in eyes with sickle cell retinopathy-related retinal detachments (RDs). METHODS: Patients who underwent surgery for sickle cell retinopathy-related RDs at the Wilmer Eye Institute or Wills Eye Hospital between 2008 and 2020 and followed for at least 6 months postoperatively were retrospectively reviewed. The primary outcome was the rate of single-surgery anatomic success and final reattachment. RESULTS: This study included 30 eyes from 28 patients (16 women and 12 men) with tractional RD (n = 13), rhegmatogenous RD (n = 1), and combined tractional RD/rhegmatogenous RD (n = 16). Mean age was 42.1 ± 15.1 years. The mean follow-up duration was 47.8 ± 34.1 months. Twenty-five (83.3%) eyes underwent pars plana vitrectomy and five (16.7%) eyes underwent pars plana vitrectomy with scleral buckling. Single-surgery anatomic success was achieved in 21 (70.0%) eyes at 6 months. Final reattachment was achieved in 28 (93.3%) eyes (22 eyes [73.3%] without tamponade). Recurrence of RDs was significantly associated with male gender (P = 0.041), absence of previous laser (P = 0.032), iatrogenic breaks (P = 0.035), retinectomy (P = 0.034), and silicone oil tamponade (P = 0.024). Overall, the logarithm of the minimum angle of resolution visual acuity improved from 1.53 ± 0.57 (Snellen equivalent, 20/678) to 1.15 ± 1.01 (20/283) at the final visit (P = 0.03); however, eyes with recurrent RD did not achieve significant visual improvement. CONCLUSION: Pars plana vitrectomy to repair sickle cell retinopathy-related RDs was effective in achieving anatomic success and improving vision in most eyes. Single-surgery anatomic success is critical for optimizing visual outcomes.
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Anemia Falciforme , Descolamento Retiniano , Recurvamento da Esclera , Acuidade Visual , Vitrectomia , Humanos , Descolamento Retiniano/cirurgia , Descolamento Retiniano/etiologia , Descolamento Retiniano/diagnóstico , Masculino , Feminino , Estudos Retrospectivos , Adulto , Acuidade Visual/fisiologia , Vitrectomia/métodos , Anemia Falciforme/complicações , Recurvamento da Esclera/métodos , Seguimentos , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem , Tamponamento Interno/métodosRESUMO
PURPOSE: To investigate predictors of the development and resolution of cystoid macular edema (CME) after rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective cross sectional study. SUBJECTS: Patients who underwent primary repair of uncomplicated RRD. METHODS: Demographics, ophthalmic history, visual acuity, RRD features, time to development/resolution of CME, OCT characteristics of CME/epiretinal membrane (ERM), type of surgery, and treatments were collected. Logistic regressions were used to identify predictors of CME development and resolution. MAIN OUTCOME MEASURES: Predictors of CME development and resolution. RESULTS: A total of 708 eyes were included, of which 55 (7.8%) developed CME. Factors associated with an increased risk of CME development included total number of retinal detachment surgeries (odds ratio [OR] 1.66 [1.24-2.23], P < 0.001), prior intraocular surgery (OR 4.43 [1.19-16.51], P = 0.03), and presence of ERM after surgery (OR 4.49 [2.30-8.74], P < 0.001). Patients undergoing pars plana vitrectomy (PPV) were more likely to develop CME compared with patients undergoing scleral buckling (SB; OR 3.09 [1.18-8.10], P = 0.02). A longer average time to CME detection was associated with lower CME resolution (OR 0.94 [0.89-0.998], P = 0.04). In patients who developed an ERM postsurgically, those who developed CME after ERM had a lower rate of resolution compared with those who developed CME before ERM (P = 0.03). CONCLUSIONS: Cystoid macular edema may be more likely to develop in patients undergoing PPV than SB, those who underwent more surgeries for RRD repair, those who had prior intraocular surgery, or those who developed an ERM after RRD repair. Resolution of CME may be affected by the time to detection of CME and ERM development. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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PURPOSE: To provide an overview of the impact of retinopathy of prematurity (ROP), and the challenges in the screening, diagnosis, and treatment of ROP worldwide. METHODS: A comprehensive search was conducted using the PubMed database from January 2011 to October 2021 using the following keywords: retinopathy of prematurity, laser, and anti-vascular endothelial growth factor (VEGF). Data on patient characteristics, ROP treatment type, and recurrence rates were collected. The countries included in these studies were classified based on 2021-2022 World Bank definitions of high, upper-middle, lower-middle, and low-income groups. Moreover, a search for surgical outcomes for ROP and screening algorithms and artificial intelligence for ROP was conducted. RESULTS: Thirty-nine studies met the inclusion criteria. ROP treatment and outcomes showed a trend towards intravitreal anti-VEGF injections as the initial treatment for ROP globally and the treatment of recurrent ROP in high-income countries. However, laser remains the treatment of choice for ROP recurrence in middle-income countries. Surgical outcomes for ROP stage 4A, 4B and 5 are similar worldwide. The incidence of ROP and ROP-related visual impairment continue to increase globally. Although telemedicine and artificial intelligence offer potential solutions to ROP screening in resource-limited areas, the current models require further optimization to reflect the global diversity of ROP patients. CONCLUSION: ROP screening and treatment paradigms vary widely based on country income group due to disparities in resources, limited access to care, and lack of universal guidelines.
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Retinopatia da Prematuridade , Recém-Nascido , Humanos , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/cirurgia , Inibidores da Angiogênese , Fator A de Crescimento do Endotélio Vascular , Inteligência Artificial , Fotocoagulação a Laser , Injeções Intravítreas , Idade GestacionalRESUMO
OBJECTIVE: To investigate practice patterns and clinical outcomes in the repair of uncomplicated rhegmatogenous retinal detachments (RRD) in a real-world setting over a 10-year period. METHODS: We compared preferences for scleral buckling (SB), pars plana vitrectomy (PPV), PPV/SB, or pneumatic retinopexy (PR) over time, and examined the 1-year single surgery anatomic success (SSAS) and best-corrected visual acuity (BCVA) at a tertiary academic institution from 2008-2018. RESULTS: Eight hundred eight eyes had RRD repair between 2008-2011 (n = 240), 2012-2014 (n = 271), and 2015-2017 (n = 297). Compared to 2008-2011, PPV was preferred over SB in 2012-2014 (OR: 2.93; 95% CI: 1.86-4.63) and 2015-2017 (OR: 5.94; 95% CI: 3.76-9.38), and over PPV/SB in 2012-2014 (OR: 2.74; 95% CI: 1.65-4.56) and 2015-2017 (OR: 3.16; 95% CI: 31.96-5.12). PR was uncommonly utilized (<10%). Younger surgeons (graduating 2010-2017) favored PPV over SB when compared to older surgeons [graduating 1984-2000 (OR: 1.77; 95% CI: 1.18-2.65) and 2001-2009 (OR 1.73; 95% CI: 1.14-2.65)], but similarly selected PPV vs. PPV/SB as their older counterparts (p > 0.05). Compared to PPV, SSAS was higher with SB (OR: 1.53; 95% CI: 1.03-2.26) and PPV/SB (OR: 2.55; 95% CI: 1.56-4.17). One-year BCVA was markedly improved compared to baseline only for eyes that achieved SSAS (p < 0.001). CONCLUSIONS: Over the past 10 years, PPV has become the favored approach to repair uncomplicated RRD and this appears to be driven by younger surgeons' preferences. Given the superior long-term SSAS in SB and PPV/SB as compared to PPV, SB and PPV/SB should be more frequently considered when determining the appropriate repair strategy for uncomplicated RRD.
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Descolamento Retiniano , Humanos , Descolamento Retiniano/cirurgia , Descolamento Retiniano/etiologia , Resultado do Tratamento , Acuidade Visual , Estudos Retrospectivos , Recurvamento da Esclera/efeitos adversos , Vitrectomia/efeitos adversosRESUMO
PURPOSE: The purpose of this study was to assess the role of combined surgical treatment of therapeutic penetrating keratoplasty and pars plana vitrectomy in the anatomical and functional outcome of infectious keratitis endophthalmitis. METHODS: This study reviewed the medical records of 4 participating centers in the United States and Mexico. This study included patients with a clinical diagnosis of infectious keratitis endophthalmitis who had been treated with an early therapeutic penetrating keratoplasty and pars plana vitrectomy as the main treatment for endophthalmitis. From each medical record, the study retrieved demographic data, relevant medical and drug history, baseline clinical manifestation of endophthalmitis, best-corrected visual acuity, and the need for enucleation/evisceration for the control of the infection or any other reason through the follow-up. RESULTS: The study included 48 patients (50.15 ± 20.6 years). The mean follow-up time was 13 ± 0.5 months. The mean best-corrected visual acuity at baseline was 2.1 ± 0.25 logarithm of the minimum angle of resolution. At month 12 was 2.09 ± 0.61 logarithm of the minimum angle of resolution ( P = 0.9). The overall prevalence of enucleation/evisceration was 8.3% (95% confidence interval: 2.32%-19.98%). The prevalence of a vision of no-light perception was 20.8% (95% confidence interval: 2.32%-19.98%). CONCLUSIONS: Combined surgery for severe cases of infectious keratitis endophthalmitis eradicates the infection in most cases, while significantly improving the overall outcomes.
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Endoftalmite , Ceratite , Humanos , Vitrectomia/métodos , Ceratoplastia Penetrante/métodos , México/epidemiologia , Resultado do Tratamento , Endoftalmite/diagnóstico , Endoftalmite/cirurgia , Endoftalmite/tratamento farmacológico , Ceratite/cirurgia , Estudos RetrospectivosRESUMO
PURPOSE: To determine the practice pattern for treating giant retinal tear (GRT) related detachments, and their anatomic and visual outcomes with pars plana vitrectomy (PPV) with or without scleral buckling (SB). DESIGN: Retrospective cohort study. SUBJECTS: Eyes with GRT detachments repaired from 2008 to 2020 with at least 6 months of follow-up from 7 institutions in North and South America, Europe, and Asia. METHODS: Eyes repaired using PPV versus PPV/SB were compared. MAIN OUTCOME MEASURES: Anatomic and functional outcomes. RESULTS: A comparable number of eyes underwent PPV (n = 101) and PPV/SB (n = 99). Except for history of developmental abnormalities, prior intraocular surgery, and lens status, no differences in baseline demographics, ocular characteristics, or intraoperative surgical adjuncts were observed. The overall single surgery anatomic success (SSAS) at 6 months and 1 year were similar between the groups (82.2% and 77.2% of PPV, and 87.9% and 85.7% of PPV/SB). When stratified by age, the 1-year SSAS rate was higher for PPV/SB (88.5%) than PPV (56.3%) (P = 0.03) for children <18 years. For both children and adults, the mean best-corrected visual acuity (BCVA) at baseline did not differ between the PPV and PPV/SB groups. However, for children, mean BCVA at 1 year was better in the PPV/SB than PPV groups (P = 0.001) while for adults, no difference was found between the 2 groups. The mean time to the first redetachment was 7.9 months in the PPV group and 5.5 months in the PPV/SB group (P = 0.8). Proliferative vitreoretinopathy was the most common cause for redetachment (70.4% of PPV and 93.8% of PPV/SB in redetached eyes; P = 0.1). Postoperative complications were also similar between the 2 groups, including ocular hypertension, epiretinal membrane, and cataract formation. CONCLUSIONS: PPV and PPV/SB are equally popular among surgeons globally for managing GRT detachments and have comparable anatomic and visual outcomes in adults. In children, PPV/SB is superior to PPV for anatomic and functional success at 1 year. In adults, the relief of traction by the GRT may reduce peripheral traction and obviate the need for an SB. However, in children, a supplemental SB can be beneficial as complete vitreous shaving and posterior hyaloid detachment, and postoperative positioning, are difficult in this group.
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Descolamento Retiniano , Perfurações Retinianas , Adulto , Criança , Humanos , Lactente , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/etiologia , Descolamento Retiniano/cirurgia , Perfurações Retinianas/complicações , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/cirurgia , Estudos Retrospectivos , Recurvamento da Esclera/efeitos adversos , Resultado do Tratamento , Acuidade Visual , Vitrectomia/efeitos adversosRESUMO
BACKGROUND: Degenerative retinoschisis is a common condition defined by the splitting of the neurosensory retina that may rarely be associated with progressive retinal detachment (RD). Here, we aim to describe the anatomic and functional outcomes of surgical treatment of progressive symptomatic retinal detachment complicating degenerative retinoschisis (PSRDCR) using pars plana vitrectomy (PPV), scleral buckle (SB), or combined PPV/SB procedure. METHODS: A retrospective chart review of patients with PSRDCR between Jan 1, 2008 and Dec 31, 2019 was conducted. Data regarding demographics, surgical approach, and anatomic/functional outcomes were collected. RESULTS: Of the 4973 charts with RD repair during the study period, 36 eyes (0.7%) had retinoschisis with RD. 18 eyes met inclusion criteria (0.4%). The median age was 54 years (range 18-74) and all eyes were phakic. All eyes had outer layer breaks (OLBs) and 16 eyes (89%) had identifiable inner layer breaks. All OLBs were posterior to the equator in charts where position was recorded (16 eyes). The single surgery anatomic success (SSAS) and final anatomical success rates were 66% (12/18) and 100%, respectively. Eyes treated with PPV/SB had an SSAS rate of 75% (9/12), while PPV and SB had SSAS rates of 66% (2/3) and 33% (1/3), respectively. CONCLUSIONS: PSRDCR is an exceedingly rare complication of degenerative retinoschisis associated with an SSAS rate lower than for uncomplicated rhegmatogenous RD. The majority of PSRDCR were repaired via combined PPV/SB in our study, and the rarity of this complication limits statistical support of an optimal surgical method in our and prior studies. The role of SB combined with PPV for PSRDCR requires further investigation.
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Pluripotent stem cells (PSCs), which include human embryonic stem cells (hESCs) and induced pluripotent stem cell (iPSC), have been used to study development of disease processes, and as potential therapies in multiple organ systems. In recent years, there has been increasing interest in the use of PSC-based transplantation to treat disorders of the retina in which retinal cells have been functionally damaged or lost through degeneration. The retina, which consists of neuronal tissue, provides an excellent system to test the therapeutic utility of PSC-based transplantation due to its accessibility and the availability of high-resolution imaging technology to evaluate effects. Preclinical trials in animal models of retinal diseases have shown improvement in visual outcomes following subretinal transplantation of PSC-derived photoreceptors or retinal pigment epithelium (RPE) cells. This review focuses on preclinical studies and clinical trials exploring the use of PSCs for retinal diseases. To date, several phase I/II clinical trials in patients with age-related macular degeneration (AMD) and Stargardt disease (STGD1) have demonstrated the safety and feasibility of PSC-derived RPE transplantation. Additional phase I/II clinical trials using PSC-derived RPE or photoreceptor cells for the treatment of AMD, STGD1, and also retinitis pigmentosa (RP) are currently in the pipeline. As this field continues to evolve, additional technologies may enhance PSC-derived cell transplantation through gene-editing of autologous cells, transplantation of more complex cellular structures such as organoids, and monitoring of transplanted cells through novel imaging technologies.
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INTRODUCTION: High-grade astrocytomas of the mesial temporal lobe may pose surgical challenges. Several approaches (trans-sylvian, subtemporal, and transcortical) have been designed to circumnavigate the critical neurovascular structures and white fiber tracts that surround this area. Considering the paucity of literature on the transcortical approach for these lesions, we describe our institutional experience with transcortical approaches to Grade III/IV astrocytomas in the mesial temporal lobe. METHODS: Between 1999 and 2009, 23 patients underwent surgery at the Johns Hopkins Medical Institutions for Grade III/IV astrocytomas involving the mesial temporal lobe (without involvement of the temporal neocortex). Clinical notes, operative records, and imaging were reviewed. RESULTS: Thirteen patients had tumors in the dominant hemisphere. All patients underwent surgery via a transcortical approach (14 via the inferior temporal gyrus and 9 via the middle temporal gyrus). Gross total resection was obtained in 92 % of the cohort. Neurological outcomes were: clinically significant stroke (2 patients), new visual deficits (2 patients), new speech deficit (1 patient); seizure control (53 %). CONCLUSIONS: In comparison to reported results in the literature for the transylvian and subtemporal approaches, the transcortical approach may provide the access necessary for a gross total resection with minimal neurological consequences. In our series of patients, there was no statistically significant difference in outcomes between the middle temporal gyrus versus the inferior temporal gyrus trajectories.
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Astrocitoma/cirurgia , Neoplasias Encefálicas/cirurgia , Procedimentos Neurocirúrgicos/métodos , Lobo Temporal/cirurgia , Adulto , Idoso , Astrocitoma/complicações , Astrocitoma/patologia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Convulsões/etiologia , Distúrbios da Fala/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Tretoquinol , Carga Tumoral , Transtornos da Visão/epidemiologiaRESUMO
Aberrant regulation of cellular extrusion can promote invasion and metastasis. Here, we identify molecular requirements for early cellular invasion using a premalignant mouse model of pancreatic cancer with conditional knockout of p120 catenin (Ctnnd1). Mice with biallelic loss of p120 catenin progressively develop high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and neoplasia accompanied by prominent acute and chronic inflammatory processes, which is mediated, in part, through NF-κB signaling. Loss of p120 catenin in the context of oncogenic Kras also promotes remarkable apical and basal epithelial cell extrusion. Abundant single epithelial cells exit PanIN epithelium basally, retain epithelial morphology, survive, and display features of malignancy. Similar extrusion defects are observed following p120 catenin knockdown in vitro, and these effects are completely abrogated by the activation of S1P/S1pr2 signaling. In the context of oncogenic Kras, p120 catenin loss significantly reduces expression of genes mediating S1P/S1pr2 signaling in vivo and in vitro, and this effect is mediated at least, in part, through activation of NF-κB. These results provide insight into mechanisms controlling early events in the metastatic process and suggest that p120 catenin and S1P/S1pr2 signaling enhance cancer progression by regulating epithelial cell invasion. Cancer Res; 76(11); 3351-63. ©2016 AACR.
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Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Cateninas/metabolismo , Células Epiteliais/patologia , Metaplasia/patologia , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Cateninas/genética , Proliferação de Células , Células Epiteliais/metabolismo , Humanos , Metaplasia/genética , Metaplasia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Células Tumorais Cultivadas , delta CateninaRESUMO
Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine repeat expansion in mutant huntingtin (mHtt). Despite the known genetic cause of HD, the pathophysiology of this disease remains to be elucidated. Inositol polyphosphate multikinase (IPMK) is an enzyme that displays soluble inositol phosphate kinase activity, lipid kinase activity, and various noncatalytic interactions. We report a severe loss of IPMK in the striatum of HD patients and in several cellular and animal models of the disease. This depletion reflects mHtt-induced impairment of COUP-TF-interacting protein 2 (Ctip2), a striatal-enriched transcription factor for IPMK, as well as alterations in IPMK protein stability. IPMK overexpression reverses the metabolic activity deficit in a cell model of HD. IPMK depletion appears to mediate neural dysfunction, because intrastriatal delivery of IPMK abates the progression of motor abnormalities and rescues striatal pathology in transgenic murine models of HD.
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Doença de Huntington/enzimologia , Doença de Huntington/fisiopatologia , Neurônios/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Adulto , Idoso , Animais , Biocatálise , Demografia , Dependovirus/metabolismo , Modelos Animais de Doenças , Estabilidade Enzimática , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Atividade Motora , Neostriado/enzimologia , Neostriado/patologia , Neostriado/fisiopatologia , Neurônios/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Mudanças Depois da Morte , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Análise de Sobrevida , Transcrição Gênica , Proteínas Supressoras de Tumor/metabolismoRESUMO
Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that mediates adaptive responses to oxygen deprivation. In addition, the HIF-1α subunit has a nontranscriptional role as a negative regulator of DNA replication through effects on minichromosome maintenance helicase loading and activation. However, some cell types continue to replicate under hypoxic conditions. The mechanism by which these cells maintain proliferation in the presence of elevated HIF-1α levels is unclear. Here we report that HIF-1α physically and functionally interacts with cyclin-dependent kinase 1 (Cdk1) and Cdk2. Cdk1 activity blocks lysosomal degradation of HIF-1α and increases HIF-1α protein stability and transcriptional activity. By contrast, Cdk2 activity promotes lysosomal degradation of HIF-1α at the G1/S phase transition. Blocking lysosomal degradation by genetic or pharmacological means leads to HIF-1α-dependent cell-cycle arrest, demonstrating that lysosomal degradation of HIF-1α is an essential step for the maintenance of cell-cycle progression under hypoxic conditions.
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Proteína Quinase CDC2/metabolismo , Pontos de Checagem do Ciclo Celular/fisiologia , Quinase 2 Dependente de Ciclina/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lisossomos/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/fisiologia , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , ProteóliseRESUMO
Profound induction of immediate early genes (IEGs) by neural activation is a critical determinant for plasticity in the brain, but intervening molecular signals are not well characterized. We demonstrate that inositol polyphosphate multikinase (IPMK) acts noncatalytically as a transcriptional coactivator to mediate induction of numerous IEGs. IEG induction by electroconvulsive stimulation is virtually abolished in the brains of IPMK-deleted mice, which also display deficits in spatial memory. Neural activity stimulates binding of IPMK to the histone acetyltransferase CBP and enhances its recruitment to IEG promoters. Interestingly, IPMK regulation of CBP recruitment and IEG induction does not require its catalytic activities. Dominant-negative constructs, which prevent IPMK-CBP binding, substantially decrease IEG induction. As IPMK is ubiquitously expressed, its epigenetic regulation of IEGs may influence diverse nonneural and neural biologic processes.
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Encéfalo/metabolismo , Epigênese Genética/fisiologia , Regulação da Expressão Gênica/fisiologia , Genes Precoces/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ativação Transcricional/fisiologia , Análise de Variância , Animais , Proteína de Ligação a CREB/metabolismo , Imunoprecipitação da Cromatina , Regulação da Expressão Gênica/genética , Genes Precoces/genética , Aprendizagem em Labirinto , Camundongos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Reconhecimento Psicológico/fisiologiaRESUMO
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that mediates adaptive responses to hypoxia. We demonstrate that lysosomal degradation of the HIF-1α subunit by chaperone-mediated autophagy (CMA) is a major regulator of HIF-1 activity. Pharmacological inhibitors of lysosomal degradation, such as bafilomycin and chloroquine, increased HIF-1α levels and HIF-1 activity, whereas activators of chaperone-mediated autophagy, including 6-aminonicotinamide and nutrient starvation, decreased HIF-1α levels and HIF-1 activity. In contrast, macroautophagy inhibitors did not increase HIF-1 activity. Transcription factor EB, a master regulator of lysosomal biogenesis, also negatively regulated HIF-1 activity. HIF-1α interacts with HSC70 and LAMP2A, which are core components of the CMA machinery. Overexpression of HSC70 or LAMP2A decreased HIF-1α protein levels, whereas knockdown had the opposite effect. Finally, hypoxia increased the transcription of genes involved in CMA and lysosomal biogenesis in cancer cells. Thus, pharmacological and genetic approaches identify CMA as a major regulator of HIF-1 activity and identify interplay between autophagy and the response to hypoxia.