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1.
Cell Biochem Funct ; 39(2): 235-247, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32996618

RESUMEN

The p53 tumour suppressor is considered one of the most critical genes in cancer biology. By upregulating apoptosis, cell cycle arrest, and DNA damage repair in normal cells, p53 prevents the propagation of cells with tumorigenic potential; therefore, mutations in p53 are associated with carcinogenic transformation and can be accompanied by the accumulation of a novel gain-of-function oncogenic protein, mutant p53. Although p53 is most often understood to utilize context-dependent post-translational modifications to achieve regulation of its many target genes, recent research has also sought to define other mechanisms of regulating p53 gene expression prior to translation and to understand how this alternative regulation of p53 may influence target gene expression and cellular outcome. This review attempts to summarize what is known about p53 regulation at the transcriptional, post-transcriptional, and post-translational levels while paying special attention to the ways in which context may influence p53 regulation and subsequent regulation of its target genes.


Asunto(s)
Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/genética , Puntos de Control del Ciclo Celular , Transformación Celular Neoplásica , Reparación del ADN , Regulación de la Expresión Génica , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Procesamiento Proteico-Postraduccional , Proteína p53 Supresora de Tumor/genética
2.
Mol Carcinog ; 58(11): 1960-1973, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31355511

RESUMEN

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.


Asunto(s)
Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Pleurales/genética , Fumar/efectos adversos , Factores de Transcripción/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/patología , Mesotelioma Maligno , Persona de Mediana Edad , Neoplasias Pleurales/patología , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Regiones Promotoras Genéticas , Factores de Riesgo , Fumar/genética
3.
Mol Carcinog ; 57(1): 106-113, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28892201

RESUMEN

Polymorphisms in the promoter of the BRM gene, a critical subunit of the chromatin remodeling SWI/SNF complex, have previously been implicated in risk and prognosis in Caucasian-predominant lung, head and neck, esophageal, and pancreatic cancers, and in hepatocellular cancers in Asians. We investigated the role of these polymorphisms in hepatocellular carcinoma (HCC) risk and prognosis. HCC cases were recruited in a comprehensive cancer center while the matched controls were recruited from family practice units from the same catchment area. For risk analyses, unconditional logistic regression analyses were performed in HCC patients and matched healthy controls. Overall survival analyses were performed using Cox proportional hazard models, Kaplan-Meier curves, and log-rank tests. In 266 HCC cases and 536 controls, no association between either BRM promoter polymorphism (BRM-741 or BRM-1321) and risk of HCC was identified (P > 0.10 for all comparisons). There was significant worsening of overall survival as the number of variant alleles increased: BRM-741 per variant allele adjusted hazards ratio (aHR) 5.77, 95% confidence interval (CI) 2.89-11.54 and BRM-1321 per variant allele aHR 4.09, 95%CI 2.22-7.51. The effects of these two polymorphisms were at least additive, where individuals who were double homozygotes for the variant alleles had a 45-fold increase in risk of death when compared to those who were double wild-type for the two polymorphisms. Two BRM promoter polymorphisms were strongly associated with HCC prognosis but were not associated with increased HCC susceptibility. The association was strongest in double homozygotes for the allele variants.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Femenino , Genotipo , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Adulto Joven
4.
Int J Cancer ; 139(11): 2474-81, 2016 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-27487558

RESUMEN

Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.


Asunto(s)
Neoplasias Pancreáticas/genética , Factores de Transcripción/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Factores de Edad , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Neoplasias Pancreáticas/mortalidad , Polimorfismo Genético , Pronóstico , Regiones Promotoras Genéticas , Factores Sexuales , Análisis de Supervivencia
5.
Carcinogenesis ; 35(10): 2183-93, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24876151

RESUMEN

Flavonoids have been extensively studied and are well documented to have anticancer effects, but it is not entirely known how they impact cellular mechanisms to elicit these effects. In the course of this study, we found that a variety of different flavonoids readily restored Brahma (BRM) in BRM-deficient cancer cell lines. Flavonoids from each of the six different structural groups were effective at inducing BRM expression as well as inhibiting growth in these BRM-deficient cancer cells. By blocking the induction of BRM with shRNA, we found that flavonoid-induced growth inhibition was BRM dependent. We also found that flavonoids can restore BRM functionality by reversing BRM acetylation. In addition, we observed that an array of natural flavonoid-containing products both induced BRM expression as well as deacetylated the BRM protein. We also tested two of the BRM-inducing flavonoids (Rutin and Diosmin) at both a low and a high dose on the development of tumors in an established murine lung cancer model. We found that these flavonoids effectively blocked development of adenomas in the lungs of wild-type mice but not in that of BRMnull mice. These data demonstrate that BRM expression and function are regulated by flavonoids and that functional BRM appears to be a prerequisite for the anticancer effects of flavonoids both in vitro and in vivo.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Flavonoides/farmacología , Factores de Transcripción/metabolismo , Acetilación/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/química , Línea Celular Tumoral/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Flavonoides/química , Humanos , Ratones , Ratones Mutantes , Terapia Molecular Dirigida , Fosforilación/efectos de los fármacos , ARN Interferente Pequeño , Proteína de Retinoblastoma/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Factores de Transcripción/genética
6.
J Environ Manage ; 140: 135-44, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24747936

RESUMEN

Mining-influenced water emanating from mine tailings and potentially contaminating surface water and groundwater is one of the most important environmental issues linked to the mining industry. In this study, two subsets of Callahan Mine tailings (mainly comprised of silicates, sulfides, and carbonates) were collected using sealed containers, which allowed keeping the samples under anoxic conditions during transportation and storage. Among the potential contaminants, in spite of high concentrations of Cu, Mn, Pb, and Zn present in the solid mine tailings, only small amounts of Mn and Zn were found in the overlying pore water. The samples were subjected to leaching tests at different reduction-oxidation (redox) conditions to compare metal and S mobilization under oxic and anoxic conditions. It was observed that Cd, Cu, Mn, Pb, S, and Zn were mobilized at higher rates under oxic conditions, while Fe was mobilized at a higher rate under anoxic conditions in comparable constant pH experiments. These results suggest that metal mobilization is significantly impacted by redox conditions. When anoxic metal mobilization assessment is required, it is recommended to always maintain anoxic conditions because oxygen exposure may affect metal mobilization. A sequential extraction performed under oxic conditions revealed that most of the metals in the samples were associated with the sulfidic fraction and that the labile fraction was associated with Mn and moderate amounts of Pb and Zn.


Asunto(s)
Residuos Industriales/análisis , Metales/análisis , Minería , Contaminantes Químicos del Agua/análisis , Carbonatos , Monitoreo del Ambiente , Maine , Oxígeno/química , Silicatos , Sulfuros
7.
Carcinogenesis ; 34(5): 1012-7, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23322154

RESUMEN

The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM-741 and BRM-1321) have been correlated with BRM loss and elevated cancer risk. The aim(s) of this study were to examine BRM expression in head and neck squamous cell carcinoma (HNSCC) and to correlate BRM polymorphisms with HNSCC risk. BRM expression studies were performed on eight HNSCC cell lines and 76 surgically resected tumor samples. A case-control study was conducted on 668 HNSCC patients (oral cavity, oropharynx, larynx and hypopharynx) and 700 healthy matched controls. BRM expression was lost in 25% of cell lines and 16% of tumors. The homozygous genotype of each polymorphism was significantly associated with increased HNSCC risk [BRM-741: adjusted odds ratio (aOR) 1.75, 95% CI 1.2-2.3, P < 0.001; BRM-1321: aOR 1.65, 95% CI 1.2-2.2, P < 0.001]. Individuals that were homozygous for both BRM polymorphisms had a more than 2-fold increase in the risk of HNSCC (aOR 2.23, 95% CI 1.5-3.4, P < 0.001). A particularly elevated risk was seen within the oropharynx, human papillomavirus-positive subgroup for carriers of both homozygous variants (aOR 3.09, 95% CI 1.5-6.8, P = 0.004). BRM promoter polymorphisms appear to act as susceptibility markers of HNSCC with potential utility in screening, prevention and treatment.


Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Factores de Transcripción/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Predisposición Genética a la Enfermedad , Genotipo , Homocigoto , Humanos , Polimorfismo Genético , Regiones Promotoras Genéticas , Carcinoma de Células Escamosas de Cabeza y Cuello
8.
Exp Mol Pathol ; 94(1): 262-9, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23103611

RESUMEN

Our previous studies have revealed that the human FOXF1 gene, encoding a transcription factor member of the forkhead box (FOX) family, functions as a tumor suppressor and its expression is frequently silenced in breast cancer via DNA hypermethylation. Moreover, we recently reported that FOXF1 expression is preferentially silenced in colorectal cancer cell lines with inactive p53 and knockdown of FOXF1 caused genomic instability in FOXF1-expressing colorectal cancer cells with a defect in the p53-p21(WAF1) checkpoint, suggesting that FOXF1 plays a key role in colorectal tumorigenesis. Given that the in vivo role of FOXF1 in colorectal cancer remains unknown, the study here was aimed at delineating the clinical relevance of FOXF1 in colorectal adenocarcinomas. To characterize FOXF1 protein expression in colorectal cancer, designed tissue microarrays, comprising 50 cases of primary colorectal adenocarcinoma paired with matched adjacent normal tissue, were utilized in the immunohistochemistry (IHC) study. The IHC results showed that for adjacent normal colorectal tissue, the FOXF1 protein was only detected in stroma, not in epithelium, with either cytoplasmic staining (70% of total cases) or a mix of cytoplasmic and nuclear staining (6%). In contrast, for colorectal adenocarcinomas, FOXF1 staining was predominately identified in the cytoplasm of tumor epithelial cells (40% of total cases) and tumor-associated stromal cells of some cases (10%) also exhibited FOXF1 positivity in their cytoplasm. Cytoplasmic FOXF1 protein expression in tumor epithelial cells positively correlated with the histologic grade, depth of invasion, stage and lymphatic metastasis of colorectal adenocarcinomas (p<0.05). Moreover, in silico meta-analysis of Oncomine's cancer microarray database indicates that FOXF1 mRNA is overexpressed in a significant subset of colorectal adenocarcinoma tumors compared with normal colorectal tissue and other types of cancers. Our findings for the first time have revealed that the FOXF1 protein is overexpressed as well as mislocalized in cancerous epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts of colorectal adenocarcinomas, and suggest that FOXF1 is a potential prognostic marker due to its association with the malignancy and metastasis of colorectal cancer.


Asunto(s)
Adenocarcinoma/metabolismo , Neoplasias Colorrectales/metabolismo , Citoplasma/metabolismo , Factores de Transcripción Forkhead/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/secundario , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Metilación de ADN , Femenino , Fibroblastos/metabolismo , Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metástasis de la Neoplasia , Pronóstico , ARN Mensajero/biosíntesis , Células del Estroma/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
9.
Exp Cell Res ; 318(16): 1973-86, 2012 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-22721696

RESUMEN

Chromatin remodeling complex SWI/SNF plays important roles in many cellular processes including transcription, proliferation, differentiation and DNA repair. In this report, we investigated the role of SWI/SNF catalytic subunits Brg1 and Brm in the cellular response to cisplatin in lung cancer and head/neck cancer cells. Stable knockdown of Brg1 and Brm enhanced cellular sensitivity to cisplatin. Repair kinetics of cisplatin DNA adducts revealed that downregulation of Brg1 and Brm impeded the repair of both intrastrand adducts and interstrand crosslinks (ICLs). Cisplatin ICL-induced DNA double strand break repair was also decreased in Brg1 and Brm depleted cells. Altered checkpoint activation with enhanced apoptosis as well as impaired chromatin relaxation was observed in Brg1 and Brm deficient cells. Downregulation of Brg1 and Brm did not affect the recruitment of DNA damage recognition factor XPC to cisplatin DNA lesions, but affected ERCC1 recruitment, which is involved in the later stages of DNA repair. Based on these results, we propose that SWI/SNF chromatin remodeling complex modulates cisplatin cytotoxicity by facilitating efficient repair of the cisplatin DNA lesions.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Cromosómicas no Histona/antagonistas & inhibidores , Cisplatino/farmacología , ADN Helicasas/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Cromatina/efectos de los fármacos , Cromatina/genética , Cromatina/metabolismo , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Ensamble y Desensamble de Cromatina/genética , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Aductos de ADN/genética , ADN Helicasas/genética , ADN Helicasas/metabolismo , Reparación del ADN , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Endonucleasas/antagonistas & inhibidores , Endonucleasas/genética , Endonucleasas/metabolismo , Técnicas de Silenciamiento del Gen , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
10.
Disaster Med Public Health Prep ; 16(2): 791-800, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-33750505

RESUMEN

Disasters have many deleterious effects and are becoming more frequent. From a health-care perspective, disasters may cause periods of stress for hospitals and health-care systems. Telemedicine is a rapidly growing technology that has been used to improve access to health-care during disasters. Telemedicine applied in disasters is referred to as disaster telemedicine. Our objective was to conduct a scoping literature review on current use of disaster telemedicine to develop recommendations addressing the most common barriers to implementation of a telemedicine system for regional disaster health response in the United States. Publications on telemedicine in disasters were collected from online databases. This included both publications in English and those translated into English. Predesigned inclusion/exclusion criteria and a PRISMA flow diagram were applied. The PRISMA flow diagram was used on the basis that it would help streamline the available literature. Literature that met the criteria was scored by 2 reviewers who rated relevance to commonly identified disaster telemedicine implementation barriers, as well as how disaster telemedicine systems were implemented. We also identified other frequently mentioned themes and briefly summarized recommendations for those topics. Literature scoring resulted in the following topics: telemedicine usage (42 publications), system design and operating models (43 publications), as well as difficulties with credentialing (5 publications), licensure (6 publications), liability (4 publications), reimbursement (5 publications), and technology (24 publications). Recommendations from each category were qualitatively summarized.


Asunto(s)
Desastres , Telemedicina , Atención a la Salud , Humanos , Estados Unidos
11.
Apoptosis ; 16(9): 950-8, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21710255

RESUMEN

p53 induces the transcription of genes that negatively regulate progression of the cell cycle in response to DNA damage or other cellular stressors, and thus participates in maintaining genome stability. Under stress conditions, p53 must be activated to prohibit the replication of cells containing damaged DNA. However, in normal, non-stressed cells, p53 activity must be inhibited. Previous studies have demonstrated that p53 transcription is activated before or during early S-phase in cells progressing from G(0)/G(1) into S-phase. Since this is not what would be predicted from a gene involved in growth arrest and apoptosis, in this study, we provide evidence that this induction occurs to provide sufficient p53 mRNA to ensure a rapid response to DNA damage before exiting S-phase. When comparing exponentially growing Swiss3T3 cells to those synchronized to enter S-phase simultaneously and treated with the DNA damaging agent camptothecin, we found that with cells in S-phase, p53 protein levels increased earlier, Bax and p21 transcription was activated earlier and to a greater extent and apoptosis occurred earlier and to a greater extent. These findings are consistent with p53 transcription being induced in S-phase to provide for a rapid DNA-damage response during S-phase of the cell cycle.


Asunto(s)
Daño del ADN , Fase S , Activación Transcripcional , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis , Camptotecina/farmacología , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Inmunoprecipitación de Cromatina , Regulación Neoplásica de la Expresión Génica , Genes p53 , Ratones , ARN Mensajero/metabolismo , Células 3T3 Swiss , Transcripción Genética , Proteína X Asociada a bcl-2/metabolismo
12.
Plasmid ; 66(3): 169-79, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21924287

RESUMEN

Analysis of numerous genomes has identified a class of regulatory regions that contain a head-to-head arrangement (5' to 5') on opposite strands of DNA. Often these regulatory regions have fewer than 1000 base pairs separating their corresponding transcription start sites and have been termed as being "bidirectional". This bidirectional arrangement and the divergent gene pairs under the control of these regulatory regions appear to be a common feature within genomes. Establishing methods to study these bidirectional transcriptional promoters, and understanding how they are regulated will allow researchers to gain more insight into the roles that divergent transcription plays in the expression and maintenance of protein coding genes. Recently, the p53 tumor suppressor gene was shown to have a bidirectional gene partner, WDR79. The transcription start sites (TSSs) of human and murine p53 and WDR79 genes are separated by approximately 800 and 930bp, respectively, in a head-to-head fashion, and fit the criteria of what is designated to be a putative bidirectional regulatory region. However, further testing is needed to demonstrate that the region between these genes contains a functional bidirectional promoter. Here, we have developed a bidirectional reporter vector, termed pLucRLuc, to study the transcriptional output of each promoter. This bidirectional reporter vector will allow researchers to determine the output of transcripts mediated by the bidirectional promoters. By focusing our studies on the transcriptional regulation of p53 and its bidirectional gene partner, WDR79, we hope to elucidate key factors that can control and regulate the expression of the p53 and WDR79 genes. Here, we demonstrate that pLucRLuc is a vector capable of expressing reporter genes under the control of bidirectional promoters in multiple human and murine cell lines and that the regulatory region upstream of the p53 and WDR79 TSSs is a bidirectional promoter controlled by common regulatory factors.


Asunto(s)
Genes Reporteros , Vectores Genéticos , Regiones Promotoras Genéticas , Proteínas/genética , Proteína p53 Supresora de Tumor/genética , Animales , Ciclo Celular/genética , Línea Celular , Regulación de la Expresión Génica , Orden Génico , Células HT29 , Células HeLa , Humanos , Ratones , Chaperonas Moleculares , Células 3T3 Swiss , Telomerasa , Activación Transcripcional
13.
Lett Drug Des Discov ; 8(1): 93-99, 2011 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-23565070

RESUMEN

Drug discovery in the field of oncology has been advanced mainly through the targeting of receptor tyrosine kinases. Both antibodies and small molecule inhibitors have been found to have successful applications in blocking the proliferative functions of these cell surface receptors. Based on these early successes, additional kinases within the cytoplasm have been found to promote cancer and, as such, have been recognized as feasible targets for additional modes of therapies. Unlike these oncogene targets, most tumor suppressors are irreversibly altered during cancer progression and therefore are not feasible targets for therapy. However, a subset of these genes is reversibly epigenetically suppressed. One such gene is BRM, and when it is re-expressed in cancer cells, this gene halts their growth. Moreover, as the key catalytic subunit of the SWI/SNF complex, BRM is centrally important to a host of anticancer pathways and cellular mechanisms, and its status may serve as a biomarker. Restoring its expression will both reconnect a number of growth-controlling pathways and affect cellular adhesion, DNA repair, and immune functions. For these reasons, restoring BRM expression is not only feasible, but potentially a potent form of anticancer therapy. To identify BRM-restoring compounds, we developed a cell-based luciferase assay. In this review, we discuss some of the challenges we encountered, issues related to this type of drug discovery, and our future ambitions. We hope this review will provide insight to this type of endeavor and lead to more investigations pursuing this type of drug research.

14.
Cell Biol Int ; 34(9): 883-91, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20446924

RESUMEN

p53 is a tumour-suppressor protein that plays a role in many cellular processes, including regulation of the cell cycle, DNA repair, transcriptional regulation of genes, chromosomal segregation, cell senescence and apoptosis. The protein's role as a transcription factor has shown that deregulated transcription, whether increased or decreased, has the potential to contribute to the formation of human cancers. It was previously reported that binding of two transcription factors, C/EBPbeta and RBP-Jkappa, to a regulatory site on the p53 promoter regulates its activity, in vitro, in a cell cycle-dependent manner. C/EBPbeta is a CCAAT enhancer-binding protein that is a member of the basic leucine zipper transcription factor (bZIP) family that plays an important role in mediating cell proliferation, differentiation and can also be involved in inflammatory responses, metabolism, cellular transformation, oncogene-induced senescence and tumorigenesis. RBP-Jkappa participates in the transcriptional regulation of target genes by interacting with the cytoplasmic domain of the Notch receptors. When RBP-Jkappa is released, transcriptional repression of its target genes occurs through the recruitment of co-repressor complexes and prevents transcription from occurring. Our reports, here and previously published, show that repression of p53 by RBP-Jkappa and activation of p53 by C/EBPbeta through differential binding of these two factors indicates a type of co-operative regulation in p53 expression. Here, we demonstrate through the use of chromatin immunoprecipitation (ChIP) assays that the co-ordinated binding of these two factors to the p53 promoter occurs in vivo and serves to regulate p53's activity during the cell cycle.


Asunto(s)
Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Inmunoprecipitación de Cromatina , Genes Supresores de Tumor , Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Regiones Promotoras Genéticas , Proteína p53 Supresora de Tumor/genética , Células 3T3 , Animales , Ensayo de Cambio de Movilidad Electroforética , Regulación de la Expresión Génica , Ratones , Unión Proteica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Fase S , Suero
15.
AEM Educ Train ; 4(2): 154-157, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32313862

RESUMEN

Physician assistants (PAs) are expanding their role in academic emergency departments (EDs). There are no published models for how to integrate PAs into departmental educational activities, scholarship, and operations outside of a PA residency approach. We created a professional development program for PAs that would provide them with opportunities to integrate into all aspects of our department mission and provide them with a forum for personal growth and ongoing education. The program provides PAs with resources including protected time and mentorship to become a content expert in an academic area of interest. We review our 5-year experience creating and implementing this program, which has grown from six PAs in 2013 to 24 PAs in 2018. These PAs now have formal roles in five of our eight divisions, participating in education, administrative, and research activities. The retention rate for PAs in this program is 90.2% versus 85.7% for PAs at our department who are not in the program. Our experience and results demonstrate the value of investing in the professional development and continued education of PAs at an academic ED versus the traditional model of service and the potential for integration into all aspects of an academic ED's mission.

16.
Mol Cancer ; 8: 4, 2009 Jan 16.
Artículo en Inglés | MEDLINE | ID: mdl-19149898

RESUMEN

BACKGROUND: CDKN2A/p16INK4a is frequently altered in human cancers and it is the most important melanoma susceptibility gene identified to date. p16INK4a inhibits pRb phosphorylation and induces cell cycle arrest, which is considered its main tumour suppressor function. Nevertheless, additional activities may contribute to the tumour suppressor role of p16INK4a and could help explain its specific association with melanoma predisposition. To identify such functions we conducted a yeast-two-hybrid screen for novel p16INK4a binding partners. RESULTS: We now report that p16INK4a interacts with the chromatin remodelling factor BRG1. We investigated the cooperative roles of p16INK4a and BRG1 using a panel of cell lines and a melanoma cell model with inducible p16INK4a expression and BRG1 silencing. We found evidence that BRG1 is not required for p16INK4a-induced cell cycle inhibition and propose that the p16INK4a-BRG1 complex regulates BRG1 chromatin remodelling activity. Importantly, we found frequent loss of BRG1 expression in primary and metastatic melanomas, implicating this novel p16INK4a binding partner as an important tumour suppressor in melanoma. CONCLUSION: This data adds to the increasing evidence implicating the SWI/SNF chromatin remodelling complex in tumour development and the association of p16INK4a with chromatin remodelling highlights potentially new functions that may be important in melanoma predisposition and chemoresistance.


Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , ADN Helicasas/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Western Blotting , Ciclo Celular/genética , Línea Celular Tumoral , Senescencia Celular/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/fisiología , ADN Helicasas/fisiología , Humanos , Inmunohistoquímica , Inmunoprecipitación , Melanoma/metabolismo , Proteínas Nucleares/fisiología , Unión Proteica , Transducción de Señal/genética , Transducción de Señal/fisiología , Factores de Transcripción/fisiología , Técnicas del Sistema de Dos Híbridos
17.
Lung Cancer ; 63(3): 433-5, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19100648

RESUMEN

We report the case of a woman with non-small cell lung cancer (NSCLC) metastatic to the pancreas who underwent pancreatic resection followed by a significant disease-free interval. Resection of NSCLC metastases, other than those to the brain and adrenal gland, are rarely reported. We could not identify any other cases of pancreatic metastasis resection in the literature. This case proves, in principle, that resection of solitary metastatic lesions in certain clinical conditions can be improved regardless of location.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/patología , Pancreatectomía/métodos , Neoplasias Pancreáticas/cirugía , Adulto , Carcinoma de Pulmón de Células no Pequeñas/secundario , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/cirugía , Neoplasias Pancreáticas/secundario
18.
Cell Biol Int ; 33(3): 318-24, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19135161

RESUMEN

The tightly regulated expression of p53 contributes to genomic stability and transcription of the p53 gene is induced prior to cells entering S-phase, possibly as a mechanism to insure a rapid p53 response in the event of DNA damage. We have previously described the cloning of an additional 1000bp of upstream p53 sequences that play a role in the regulated expression of p53, and identified that C/EBPbeta-2 participates in inducing p53 gene expression in a cell cycle regulated fashion. This report deals with the transcriptional regulator, RBP-Jkappa, an essential target of the Notch receptor signaling pathway. It binds to the p53 promoter in a cell cycle regulation fashion and also serves to repress p53 gene expression. We conclude from these findings that the coordinate expression of C/EBPbeta-2 and RBP-Jkappa may be linked to p53 transcription during G(0) and as cells move into S-phase. Because defects in the Notch signaling pathway have been implicated in carcinogenesis, aberrant RBP-Jkappa expression and deregulated regulation of the p53 tumor suppressor could be an important step in some forms of cancers.


Asunto(s)
Proteína de Unión a la Señal Recombinante J de las Inmunoglobulinas/metabolismo , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor/genética , Animales , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Células COS , Ciclo Celular , Línea Celular , Chlorocebus aethiops , Regulación hacia Abajo , Células HeLa , Humanos , Ratones , Regiones Promotoras Genéticas , Fase de Descanso del Ciclo Celular , Fase S , Células 3T3 Swiss , Transcripción Genética , Transfección , Proteína p53 Supresora de Tumor/metabolismo
20.
Environ Microbiol ; 10(8): 2087-97, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18430021

RESUMEN

The microbial communities of two field-scale pilot sulfate-reducing bioreactors treating acid mine drainage (AMD), Luttrell and Peerless Jenny King (PJK), were compared using biomolecular tools and multivariate statistical analyses. The two bioreactors were well suited for this study because their geographic locations and substrate compositions were similar while the characteristics of influent AMD, configuration and degree of exposure to oxygen were distinct. The two bioreactor communities were found to be functionally similar, including cellulose degraders, fermenters and sulfate-reducing bacteria (SRB). Significant differences were found between the two bioreactors in phylogenetic comparisons of cloned 16S rRNA genes and adenosine 5'-phosphosulfate reductase (apsA) genes. The apsA gene clones from the Luttrell bioreactor were dominated by uncultured SRB most closely related to Desulfovibrio spp., while those of the PJK bioreactor were dominated by Thiobacillus spp. The fraction of the SRB genus Desulfovibrio was also higher at Luttrell than at PJK as determined by quantitative real-time polymerase chain reaction analysis. Oxygen exposure at PJK is hypothesized to be the primary cause of these differences. This study is the first rigorous phylogenetic investigation of field-scale bioreactors treating AMD and the first reported application of multivariate statistical analysis of remediation system microbial communities applying UniFrac software.


Asunto(s)
Desulfovibrio/aislamiento & purificación , Minería , Sulfatos/metabolismo , Thiobacillus/aislamiento & purificación , Eliminación de Residuos Líquidos , Biodegradación Ambiental , Reactores Biológicos , Desulfovibrio/genética , Ecosistema , ARN Ribosómico 16S , Thiobacillus/genética
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