RESUMEN
BACKGROUND: In Ontario, Canada, approximately $2.5 billion is spent yearly on occupational injuries in the healthcare sector. The healthcare sector has been ranked second highest for lost-time injury rates among 16 Ontario sectors since 2009 with female healthcare workers ranked the highest among all occupations for lost-time claims. There is a great deal of focus in Ontario's occupational health and safety system on compliance and fines, however despite this increased focus, the injury statistics are not significantly improving. One of the keys to changing this trend is the development of a culture of healthy and safe workplaces including the effective utilization of leading indicators within Occupational Health and Safety Management Systems (OHSMSs). In contrast to lagging indicators, which focus on outcomes retrospectively, a leading indicator is associated with proactive activities and consists of selected OHSMSs program elements. Using leading indicators to measure health and safety has been common practice in high-risk industries; however, this shift has not occurred in healthcare. The aim of this project is to conduct a longitudinal study implementing six elements of the Ontario Safety Association for Community and Healthcare (OSACH) system identified as leading indicators and evaluating the effectiveness of this intervention on improving selected health and safety workplace indicators. METHODS: A quasi-experimental longitudinal research design will be used within two Ontario acute care hospitals. The first phase of the study will focus on assessing current OHSMSs using the leading indicators, determining potential facilitators and barriers to changing current OHSMSs, and identifying the leading indicators that could be added or changed to the existing OHSMS in place. Phase I will conclude with the development of an intervention designed to support optimizing current OHSMSs in participating hospitals based on identified gaps. Phase II will pilot test and evaluate the tailored intervention. DISCUSSION: By implementing specific elements to test leading indicators, this project will examine a novel approach to strengthening the occupational health and safety system. Results will guide healthcare organizations in setting priorities for their OHSMSs and thereby improve health and safety outcomes.
Asunto(s)
Personal de Salud/estadística & datos numéricos , Servicios de Salud del Trabajador/normas , Salud Laboral/normas , Traumatismos Ocupacionales/prevención & control , Administración de la Seguridad/normas , Lugar de Trabajo/normas , Absentismo , Atención a la Salud/normas , Femenino , Hospitales/estadística & datos numéricos , Humanos , Estudios Longitudinales , Masculino , Traumatismos Ocupacionales/epidemiología , Ontario/epidemiología , Proyectos Piloto , Indicadores de Calidad de la Atención de Salud , Administración de la Seguridad/organización & administración , Ausencia por Enfermedad/estadística & datos numéricosRESUMEN
Dysfunction of key miRNA pathways regulating basic cellular processes is a common driver of many cancers. However, the biological roles and/or clinical applications of such pathways in Merkel cell carcinoma (MCC), a rare but lethal cutaneous neuroendocrine (NE) malignancy, have yet to be determined. Previous work has established that miR-375 is highly expressed in MCC tumors, but its biological role in MCC remains unknown. Herein, we show that elevated miR-375 expression is a specific feature of well-differentiated MCC cell lines that express NE markers. In contrast, miR-375 is strikingly down-regulated in highly aggressive, undifferentiated MCC cell lines. Enforced miR-375 expression in these cells induced NE differentiation, and opposed cancer cell viability, migration, invasion, and survival, pointing to tumor-suppressive roles for miR-375. Mechanistically, miR-375-driven phenotypes were caused by the direct post-transcriptional repression of multiple Notch pathway proteins (Notch2 and RBPJ) linked to cancer and regulation of cell fate. Thus, we detail a novel molecular axis linking tumor-suppressive miR-375 and Notch with NE differentiation and cancer cell behavior in MCC. Our findings identify miR-375 as a putative regulator of NE differentiation, provide insight into the cell of origin of MCC, and suggest that miR-375 silencing may promote aggressive cancer cell behavior through Notch disinhibition.
Asunto(s)
Carcinoma de Células de Merkel/metabolismo , Diferenciación Celular/fisiología , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , Neoplasias Cutáneas/metabolismo , Linaje de la Célula , Regulación hacia Abajo , Humanos , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Receptor Notch2/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
Diabetes mellitus is a chronic metabolic health condition affecting millions globally. Diabetes is a growing concern among aging societies, with its prevalence increasing among those aged 65 and above. Enabling disease self-management via relevant education is part of high-quality care to improve health outcomes and minimize complications for individuals living with diabetes. Successful diabetes self-management education (DSME) programs usually require tailoring for the intended audience; however, there is limited literature about the preferences of older persons in Western countries concerning DSME. As such, a broad overview of DSME for older persons was an identified need. To map the available evidence on DSME for persons aged 65 years and older in Western countries, the JBI methodology for conducting and reporting scoping reviews was used. In this scoping review, we considered all studies about DSME for older persons with T1D and T2D in Western countries where lifestyles, risks, prevention, treatment of diabetes, and approaches to self-management and DSME are similar (e.g., North America, Western and Northern Europe and Australasia). Systematic keyword and subject heading searches were conducted in 10 databases (e.g., MEDLINE, JBI EBP) to identify relevant English language papers published from 2000 to 2022. Titles and abstracts were screened to select eligible papers for full-text reading. Full-text screening was done by four independent reviewers to select studies for the final analysis. The review identified 2,397 studies, of which 1,250 full texts were screened for eligibility. Of the final 44 papers included in the review, only one included participants' understanding of DSME. The education programs differed in their context, design, delivery mode, theoretical underpinnings, and duration. Type of research designs, outcome measures used to determine the effectiveness of DSME, and knowledge gaps were also detailed. Overall, most interventions were effective and improved clinical and behavioural outcomes. Many of the programs led to improvements in clinical outcomes and participants' quality of life; however, the content needs to be adapted to older persons according to their culture, different degrees of health literacy, preference of education (e.g., individualized or group), preference of setting, degree of frailty and independence, and comorbidities. Few studies included the voices of older persons in the design, implementation, and evaluation of DSME programs. Such experiential knowledge is vital in developing educational programs to ensure alignment with this population's preferred learning styles, literacy levels, culture, and needs-such an approach could manifest more substantive, sustained results.
Asunto(s)
Diabetes Mellitus , Automanejo , Humanos , Anciano , Anciano de 80 o más Años , Calidad de Vida , Diabetes Mellitus/epidemiología , Diabetes Mellitus/terapia , Escolaridad , Conductas Relacionadas con la SaludRESUMEN
Objectives: Providing diabetes self-management education (DSME) in an evidence-based format that is accessible and tailored to the population needs is crucial for individuals living with diabetes mellitus. Our qualitative study explores the experiences of older adults living with diabetes while residing in a rural setting. Methods: Adults aged 65 or older and residing in a rural area of Ontario completed a photovoice activity and semi-structured interviews to illustrate their experience of living with diabetes and accessing DSME. Results: Fourteen participants (11 males; mean age = 74 years) completed the photovoice activity and interview. Four main themes were identified pertaining to learning about diabetes education, the depth and breadth of learning, applying knowledge to daily life, and engaging older adults in DSME. Discussion: Diabetes self-management education should account for older adults' preferences in learning about diabetes and self-management to promote access to evidence-based information, bolster knowledge and self-management efficacy, and improve disease control.
Asunto(s)
Diabetes Mellitus , Automanejo , Masculino , Humanos , Anciano , Automanejo/educación , Diabetes Mellitus/terapia , Escolaridad , Conductas Relacionadas con la Salud , Investigación Cualitativa , AutocuidadoRESUMEN
OBJECTIVE: This scoping review will map the available evidence on diabetes self-management education programs for older adults in Western countries. INTRODUCTION: Self-management and education are crucial for controlling diabetes and its associated complications. The successful uptake of diabetes self-management education programs is not straightforward, and little is known about diabetes programs for older adults. Within this context, a broad overview of diabetes self-management education for older adults, considering all types of related evidence, is needed. INCLUSION CRITERIA: All studies in English concerning diabetes self-management education for older adults (aged 65 years and older) living with type 1 or 2 diabetes will be included. This review will not be specific to gender, sex, ethnicity, frailty, or other demographic variables. The review will be restricted to Western countries (North America, Western and Northern Europe, and Australasia), where approaches to diabetes self-management education will be similar. Studies including older adults with or without diabetes will not be considered unless they provide separate analyses for the 2 cohorts. METHODS: This scoping review will follow the JBI methodology for scoping reviews. We will conduct searches of electronic databases, including CINAHL, MEDLINE, and PubMed, from January 1, 2000, to the present to capture eligible articles. The review will consider all study designs, including quantitative, qualitative, mixed methods designs, as well as text and opinion papers, and systematic reviews that meet the inclusion criteria. After duplicates are removed, titles and abstracts will be screened independently by 2 reviewers, and the full texts will be reviewed. The screening criteria and data extraction protocol will be pilot-tested by the research team. The results will be summarized in tables accompanied by narrative text.
Asunto(s)
Diabetes Mellitus , Automanejo , Humanos , Anciano , Escolaridad , Conductas Relacionadas con la Salud , Bases de Datos Factuales , Europa (Continente)/epidemiología , Literatura de Revisión como AsuntoRESUMEN
MicroRNAs play important roles in gene regulation, and their expression is frequently dysregulated in cancer cells. In a previous study, we reported that miR-193b represses cell proliferation and regulates cyclin D1 in melanoma cells, suggesting that miR-193b could act as a tumor suppressor. Herein, we demonstrate that miR-193b also down-regulates myeloid cell leukemia sequence 1 (Mcl-1) in melanoma cells. MicroRNA microarray profiling revealed that miR-193b is expressed at a significantly lower level in malignant melanoma than in benign nevi. Consistent with this, Mcl-1 is detected at a higher level in malignant melanoma than in benign nevi. In a survey of melanoma samples, the level of Mcl-1 is inversely correlated with the level of miR-193b. Overexpression of miR-193b in melanoma cells represses Mcl-1 expression. Previous studies showed that Mcl-1 knockdown cells are hypersensitive to ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-X(L), and Bcl-w. Similarly, overexpression of miR-193b restores ABT-737 sensitivity to ABT-737-resistant cells. Furthermore, the effect of miR-193b on the expression of Mcl-1 seems to be mediated by direct interaction between miR-193b and seed and seedless pairing sequences in the 3' untranslated region of Mcl-1 mRNA. Thus, this study provides evidence that miR-193b directly regulates Mcl-1 and that down-regulation of miR-193b in vivo could be an early event in melanoma progression.
Asunto(s)
Melanoma/metabolismo , MicroARNs/fisiología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias Cutáneas/metabolismo , Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Ciclina D1/antagonistas & inhibidores , Regulación hacia Abajo , Resistencia a Antineoplásicos , Inhibidores de Crecimiento/farmacología , Humanos , Melanoma/tratamiento farmacológico , MicroARNs/metabolismo , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Nitrofenoles/farmacología , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Sulfonamidas/farmacologíaRESUMEN
Cutaneous melanoma is an aggressive form of human skin cancer characterized by high metastatic potential and poor prognosis. To better understand the role of microRNAs (miRNAs) in melanoma, the expression of 470 miRNAs was profiled in tissue samples from benign nevi and metastatic melanomas. We identified 31 miRNAs that were differentially expressed (13 up-regulated and 18 down-regulated) in metastatic melanomas relative to benign nevi. Notably, miR-193b was significantly down-regulated in the melanoma tissues examined. To understand the role of miR-193b in melanoma, functional studies were undertaken. Overexpression of miR-193b in melanoma cell lines repressed cell proliferation. Gene expression profiling identified 314 genes down-regulated by overexpression of miR-193b in Malme-3M cells. Eighteen of these down-regulated genes, including cyclin D1 (CCND1), were also identified as putative miR-193b targets by TargetScan. Overexpression of miR-193b in Malme-3M cells down-regulated CCND1 mRNA and protein by > or = 50%. A luciferase reporter assay confirmed that miR-193b directly regulates CCND1 by binding to the 3'untranslated region of CCND1 mRNA. These studies indicate that miR-193b represses cell proliferation and regulates CCND1 expression and suggest that dysregulation of miR-193b may play an important role in melanoma development.
Asunto(s)
Proliferación Celular , Ciclina D1/biosíntesis , Regulación Neoplásica de la Expresión Génica , Melanoma/metabolismo , MicroARNs/fisiología , Neoplasias Cutáneas/metabolismo , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Análisis por Conglomerados , Humanos , MicroARNs/biosíntesis , MicroARNs/metabolismo , Modelos Biológicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Approaches to overcome chemoresistance in cancer cells have involved targeting specific signaling pathways such as the phosphatidylinositol 3-kinase (PI3K) pathway, a stress response pathway known to be involved in the regulation of cell survival, apoptosis and growth. The present study determined the effect of PI3K inhibition on the clonogenic survival of human cancer cells following exposure to various chemotherapeutic agents. Treatment with the PI3K inhibitors LY294002 or Compound 15e resulted in increased survival of MDA-MB-231 breast carcinoma cells after exposure to doxorubicin, etoposide, 5-fluorouracil, and vincristine. Increased survival following PI3K inhibition was also observed in DU-145 prostate, HCT-116 colon and A-549 lung carcinoma cell lines exposed to doxorubicin. Increased cell survival mediated by LY294002 was correlated with a decrease in cell proliferation, which was linked to an increase in the proportion of cells in the G(1) phase of the cell cycle. Inhibition of PI3K signaling also resulted in higher levels of the cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27(Kip1); and knockdown of p27(kip1) with siRNA attenuated resistance to doxorubicin in cells treated with LY294002. Incubation in the presence of LY294002 after exposure to doxorubicin resulted in decreased cell survival. These findings provide evidence that PI3K inhibition leads to chemoresistance in human cancer cells by causing a delay in cell cycle; however, the timing of PI3K inhibition (either before or after exposure to anti-cancer agents) may be a critical determinant of chemosensitivity.
Asunto(s)
Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromonas/farmacología , Células Clonales , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Doxorrubicina/farmacología , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Humanos , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Interferente Pequeño/metabolismoRESUMEN
Cyclic adenosine 3', 5'-monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It acts principally through stimulation of cAMP-dependent protein kinases (PKAs) but also activates certain ion channels and guanine nucleotide exchange factors (Epacs). Metabolism of cAMP is catalysed by phosphodiesterases (PDEs). Here we identify a cAMP-responsive signalling complex maintained by the muscle-specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits Epac1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulations of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAP proteins is more intricate than previously appreciated.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Transducción de Señal , 3',5'-AMP Cíclico Fosfodiesterasas/genética , Animales , Línea Celular , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Citocinas/metabolismo , Humanos , Hipertrofia/inducido químicamente , Proteína Quinasa 7 Activada por Mitógenos/metabolismo , Complejos Multiproteicos/química , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Miocardio/metabolismo , Miocardio/patología , RatasRESUMEN
RATIONALE & OBJECTIVE: Cultural Safety is being prioritized within health care around the world. As a concept, Cultural Safety centers upon power relations between health providers and indigenous recipients of care, ensuring that all people feel safe and respected in the health care system. In this article, we explored the breadth of the literature regarding Cultural Safety within the context of indigenous kidney health care. STUDY DESIGN & POPULATIONS: As a systematic narrative review, this work engaged widely across a diverse range of the available literature to broaden understanding of Cultural Safety within indigenous kidney health care and indigenous populations from Australia, New Zealand, Canada, and the United States. SEARCH STRATEGY & ANALYTICAL APPROACH: Guided by the research question focused on how Cultural Safety occurs within care for indigenous people with kidney disease, an initial database search by the university librarian resulted in retrieval of 2,232 articles, of which 96 potential articles were screened by the research team. RESULTS: 15 articles relevant to the research question were identified and study findings were assembled within 3 broad clusters: relationality, engagement, and health care self-determination; systemic issues, barriers, and access; and addressing legacies of colonialism for health care providers. LIMITATIONS: The review summarizes mainly qualitative articles given the paucity of articles found specific to Cultural Safety within indigenous contexts. CONCLUSIONS: Of particular interest to health care providers are the collation of solutions by cluster and the findings of this review that contribute to further understanding of the concept of Cultural Safety in health care for indigenous people with kidney disease. Also, findings address the importance of community-driven kidney care in which language, ways of knowing and being, and traditional ways of healing are prioritized.
RESUMEN
BACKGROUND: Advances in healthcare delivery have allowed for the increase in the number of ambulatory surgery procedures performed in Canada. Despite these advances, patients return to hospital following discharge. However, the reason for unplanned healthcare use after ambulatory surgery in Canada is not well understood. AIMS: To examine unplanned healthcare use, specifically emergency department visit and hospital admissions, in the 3 days after ambulatory surgery in Ontario, Canada. METHODS: This population-based retrospective cohort study was conducted using de-identified administrative databases. Participants were residents in the province of Ontario, Canada; 18 years and older; and underwent common ambulatory surgical procedures between 2014 and 2018. The outcomes included emergency department (ED) visit and hospital admission. Incidence rates were calculated for the total cohort, for each patient characteristic and for surgical category. The odds ratios and 95% confidence intervals were calculated for each outcome using bivariate and multivariate logistic regression. RESULTS: 484,670 adults underwent select common surgical procedures during the study period. Patients had healthcare use in the first 3 days after surgery, with 14,950 (3.1%) ED visits and 14,236 (2.9%) admissions. The incidence of ED use was highest after tonsillectomy (8.1%), cholecystectomy (4.2%) and appendectomy (4.0%). Incidence of admissions was highest after appendectomy (21%). Acute pain (19.7%) and haemorrhage (14.2%) were the most frequent reasons for an ED visit and "convalescence following surgery" (49.2%) followed by acute pain (6.2%) and haemorrhage (4.5%) were the main reasons for admission. CONCLUSIONS: These findings can assist clinicians in identifying and intervening with patients at risk of healthcare use after ambulatory surgery. Pain management strategies that can be tailored to the patient, and earlier follow-up for some patients may be required. In addition, administrative decision-makers could use the results to estimate the impact of specific ambulatory procedures on hospital resources for planning and allocation of resources.
RESUMEN
Hypoxia in solid tumors is associated with the development of chemoresistance. Although many studies have focused on the effect of hypoxia on drug-induced apoptosis, the effect of nonapoptotic pathways on hypoxia-induced drug resistance has not been previously investigated. Here, we determined the effects of hypoxia on multiple forms of drug-induced death in human MDA-MB-231 breast carcinoma cells. Clonogenic assays showed that preexposure to hypoxia leads to resistance to various classes of chemotherapeutic agents, including anthracyclines (daunorubicin and doxorubicin), epipodophyllotoxins (etoposide), and anthracenediones (mitoxantrone). Results revealed a high degree of heterogeneity in nuclear and cytoplasmic alterations in response to acute drug exposure; however, the majority of exposed cells displayed morphologic and biochemical changes consistent with drug-induced senescence. Hypoxia decreased only the proportion of cells in the senescent population, whereas the small proportion of cells exhibiting features of apoptosis or mitotic catastrophe were unaffected. Similar results were obtained with human HCT116 colon carcinoma cells, indicating that the protective effect of hypoxia on drug-induced senescence is not unique to MDA-MB-231 cells. Treatment of MDA-MB-231 cells with small interfering RNA targeting the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), a key regulator of cellular adaptations to hypoxia, prevented hypoxia-induced resistance. HIF-1alpha small interfering RNA also selectively abolished the hypoxia-induced changes in the senescent population, indicating that the increased survival was due to protection against drug-induced senescence. These results support a requirement for HIF-1 in the adaptations leading to drug resistance and reveal that decreased drug-induced senescence is also an important contributor to the development of hypoxia-induced resistance.
Asunto(s)
Antineoplásicos/farmacología , Senescencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Factor 1 Inducible por Hipoxia/metabolismo , Apoptosis/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Doxorrubicina/farmacología , Humanos , Fenotipo , ARN Interferente Pequeño/metabolismo , Estaurosporina/farmacología , Ensayo de Tumor de Célula MadreRESUMEN
A novel isoform of Cbl-associated protein (CAP) was identified in a yeast two-hybrid screen for A-kinase anchoring proteins expressed in the heart. CAP is a scaffold protein implicated in insulin signaling and cytoskeleton regulation. The protein kinase A binding site is encoded by a previously unidentified, alternatively spliced exon.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Microfilamentos/metabolismo , Empalme Alternativo , Secuencia de Aminoácidos , Secuencia de Bases , Sitios de Unión , Proteínas Quinasas Dependientes de AMP Cíclico/genética , Exones , Humanos , Proteínas de Microfilamentos/genética , Datos de Secuencia Molecular , Miocardio/enzimología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Dominios Homologos srcRESUMEN
Muscle A-kinase anchoring protein (mAKAP) is a scaffold protein found principally at the nuclear envelope of striated myocytes. mAKAP maintains a complex consisting of multiple signal transduction molecules including the cAMP-dependent protein kinase A, the ryanodine receptor calcium release channel, phosphodiesterase type 4D3, and protein phosphatase 2A. By an unknown mechanism, a domain containing spectrin repeats is responsible for targeting mAKAP to the nuclear envelope. We now demonstrate that the integral membrane protein nesprin-1alpha serves as a receptor for mAKAP on the nuclear envelope in cardiac myocytes. Nesprin-1alpha is inserted into the nuclear envelope by a conserved, C-terminal, klarsicht-related transmembrane domain and forms homodimers by the binding of an amino-terminal spectrin repeat domain. Through the direct binding of the nesprin-1alpha amino-terminal dimerization domain to the third mAKAP spectrin repeat, nesprin-1alpha targets mAKAP to the nuclear envelope. In turn, overexpression of these spectrin repeat domains in myocytes can displace mAKAP from nesprin-1alpha.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Miocitos Cardíacos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Membrana Nuclear/metabolismo , Proteínas Nucleares/metabolismo , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Proteínas de Anclaje a la Quinasa A , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Sustitución de Aminoácidos , Animales , Secuencia de Bases , Unión Competitiva , Células COS , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , ADN Complementario/genética , Dimerización , Complejos Multiproteicos , Mutagénesis Sitio-Dirigida , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/química , Proteínas Nucleares/genética , Mutación Puntual , Estructura Cuaternaria de Proteína , Ratas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal , TransfecciónRESUMEN
Maladaptive cardiac hypertrophy can progress to congestive heart failure, a leading cause of morbidity and mortality in the United States. A better understanding of the intracellular signal transduction network that controls myocyte cell growth may suggest new therapeutic directions. mAKAP is a scaffold protein that has recently been shown to coordinate signal transduction enzymes important for cytokine-induced cardiac hypertrophy. We now extend this observation and show mAKAP is important for adrenergic-mediated hypertrophy. One function of the mAKAP complex is to facilitate cAMP-dependent protein kinase A-catalyzed phosphorylation of the ryanodine receptor Ca2+-release channel. Experiments utilizing inhibition of the ryanodine receptor, RNA interference of mAKAP expression and replacement of endogenous mAKAP with a mutant form that does not bind to protein kinase A demonstrate that the mAKAP complex contributes to pro-hypertrophic signaling. Further, we show that calcineurin Abeta associates with mAKAP and that the formation of the mAKAP complex is required for the full activation of the pro-hypertrophic transcription factor NFATc. These data reveal a novel function of the mAKAP complex involving the integration of cAMP and Ca2+ signals that promote myocyte hypertrophy.