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1.
Cell Death Differ ; 20(2): 312-20, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22996684

RESUMEN

The process of somatic cell reprogramming is gaining increasing interest as reprogrammed cells are considered to hold a great therapeutic potential. However, with current technologies this process is relatively inefficient. Recent studies reported that inhibition of the p53 tumor suppressor profoundly facilitates reprogramming and attributed this effect to the ability of p53 to restrict proliferation and induce apoptosis. Given that mesenchymal-to-epithelial transition (MET) was recently shown to be necessary for reprogramming of fibroblasts, we investigated whether p53 counteracts reprogramming by affecting MET. We found that p53 restricts MET during the early phases of reprogramming and that this effect is primarily mediated by the ability of p53 to inhibit Klf4-dependent activation of epithelial genes. Moreover, transcriptome analysis revealed a large transcriptional signature enriched with epithelial genes, which is markedly induced by Klf4 exclusively in p53(-/-) cells. We also found that the expression of the epithelial marker E-Cadherin negatively correlates with p53 activity in a variety of mesenchymal cells even before the expression of reprogramming factors. Finally, we demonstrate that the inhibitory effect of p53 on MET is mediated by p21. We conclude that inhibition of the p53-p21 axis predisposes mesenchymal cells to the acquisition of epithelial characteristics and renders them more prone to reprogramming. Our study uncovers a novel mechanism by which p53 restrains reprogramming and highlights the role of p53 in regulating cell plasticity.


Asunto(s)
Transición Epitelial-Mesenquimal , Proteína p53 Supresora de Tumor/metabolismo , Animales , Cadherinas/genética , Cadherinas/metabolismo , Células Cultivadas , Reprogramación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/antagonistas & inhibidores , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Endogámicos C57BL , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética
2.
Cell Death Differ ; 18(2): 271-81, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20689556

RESUMEN

A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53(R175H) mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53(R175H), was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53(R175H) mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53(R175H) mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.


Asunto(s)
Transición Epitelial-Mesenquimal , Proteínas Nucleares/metabolismo , Neoplasias de la Próstata/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Sustitución de Aminoácidos , Línea Celular Transformada , Línea Celular Tumoral , Epigénesis Genética , Histonas/metabolismo , Humanos , Masculino , Mutación , Proteínas Nucleares/genética , Complejo Represivo Polycomb 1 , Regiones Promotoras Genéticas , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/fisiología , Proteína 1 Relacionada con Twist/genética , Regulación hacia Arriba
3.
Virology ; 265(2): 286-95, 1999 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-10600600

RESUMEN

We describe the in vitro selection and characterisation of virus derived from B/Beijing/1/87 passaged in the presence of zanamivir. During zanamivir passage, the phenotype of virus isolates was either drug dependent or drug resistant in plaque reduction assays. The susceptibility of the neuraminidase of the drug-dependent isolates was unchanged from that of the wild-type enzyme. The drug-dependent isolates contained two mutations in the viral haemagglutinin: V90A, close to the proposed secondary sialic acid-binding site, and L240Q, close to the primary sialic acid-binding site. Virus isolates that were drug resistant contained the same mutations in the haemagglutinin but also contained the mutation E116G in the neuraminidase. For the drug-dependent viruses, zanamivir susceptibility could not be measured because plaque numbers increased with increasing drug concentration. The in vitro zanamivir susceptibility of drug-resistant viruses was lower than that of the wild-type virus by a factor of 275- to >2532-fold. Neuraminidase containing the E116G mutation has a 33-fold lower affinity for zanamivir than the wild-type enzyme. The finding that the same haemagglutinin mutations are found in both drug-dependent and drug-resistant viruses confirms that the same changes to the receptor binding function can contribute to both phenotypes. This observation demonstrates the interplay between the influenza virus haemagglutinin and neuraminidase in escape from zanamivir inhibition in vitro.


Asunto(s)
Antivirales/farmacología , Virus de la Influenza B/efectos de los fármacos , Ácidos Siálicos/farmacología , Animales , Línea Celular , Perros , Farmacorresistencia Microbiana , Guanidinas , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Virus de la Influenza B/genética , Virus de la Influenza B/crecimiento & desarrollo , Virus de la Influenza B/aislamiento & purificación , Modelos Moleculares , Neuraminidasa/genética , Neuraminidasa/metabolismo , Conformación Proteica , Piranos , Zanamivir
4.
Syst Biol ; 48(1): 21-30, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12078642

RESUMEN

Recent molecular studies are inconsistent with ungulate phylogenetic trees that are based on morphological traits. These inconsistencies especially relate to the position of cetaceans and perissodactyls. Evaluation of the close phylogenetic ties between artiodactyls and cetaceans has been hampered by the absence of tarsal bones of primitive cetaceans, as artiodactyls are often diagnosed on the basis of their tarsus. We here describe newly discovered tarsal bones that are the oldest cetacean tarsals known. We present a character analysis for primitive ungulate tarsals and evaluate their impact on the ungulate phylogenetic tree. Tarsal data are consistent with some molecular studies in suggesting that the extant sister group of Cetacea is Artiodactyla or that Cetacea should be included within the latter order. Tarsal data do not support Cete (Mesonychia plus Cetacea) and are consistent with the exclusion of perissodactyls from paenungulates as suggested by some molecular studies.


Asunto(s)
Cetáceos/anatomía & histología , Articulaciones/anatomía & histología , Filogenia , Rumiantes/anatomía & histología , Animales , Cetáceos/clasificación , Miembro Posterior/anatomía & histología , Rumiantes/clasificación
6.
J Med Chem ; 41(6): 787-97, 1998 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-9526555

RESUMEN

4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Neuraminidasa/antagonistas & inhibidores , Piranos/farmacología , Ácidos Siálicos/farmacología , Administración Intranasal , Animales , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Guanidinas/síntesis química , Guanidinas/química , Guanidinas/farmacocinética , Virus de la Influenza A/enzimología , Virus de la Influenza B/enzimología , Inyecciones Intraperitoneales , Ratones , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/enzimología , Piranos/síntesis química , Piranos/química , Piranos/farmacocinética , Ácidos Siálicos/química , Ácidos Siálicos/farmacocinética , Relación Estructura-Actividad , Zanamivir
7.
Bioorg Med Chem Lett ; 8(19): 2623-8, 1998 Oct 06.
Artículo en Inglés | MEDLINE | ID: mdl-9873592

RESUMEN

A series of biaryl acids has been found to show micromolar inhibition of the HIV reverse transcriptase (RT) from types 1 and 2 with IC50S in the micromolar range. The series was discovered by consideration of the polymerase active site and sub-structure searching of the company compound collection. Synthesis of analogues to investigate the SAR is described. Two of these compounds have shown inhibition of HIV-2 RT only.


Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , ADN Polimerasa Dirigida por ARN/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/síntesis química , Ácidos Carboxílicos/síntesis química , Hidrocarburos Aromáticos/síntesis química , Hidrocarburos Aromáticos/química , Hidrocarburos Aromáticos/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Relación Estructura-Actividad
8.
Anal Biochem ; 216(1): 89-96, 1994 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8135370

RESUMEN

In order to identify a suitable peptide substrate for human immunodeficiency virus-1 (HIV-1) proteinase, a range of peptides from various cleavage sites within the gag-pol polyprotein were assayed by HPLC for specific cleavage. The peptide with the optimal combination of favorable kinetics and good solubility was based on the N-terminus cleavage site of HIV-1 proteinase (KQGTVSFNF*PQIT). The HPLC assay, using the above peptide, was developed into a rapid isocratic method in order to analyze inhibition kinetics. An assay suitable for high-throughput screening was developed using a radioactively labeled peptide with the same sequence, coupled to a solid phase. Using this assay, a C2-symmetric HIV-1 proteinase inhibitor derived from penicillin was discovered during random screening of a compound library. A chemical synthesis program developed this structure into a series of potent inhibitors. The lead structures were highly selective for HIV-1 proteinase with good antiviral activity in vitro against HIV and no cytotoxicity. The HPLC assay was used to demonstrate that these compounds are competitive tight-binding inhibitors of HIV-1 proteinase.


Asunto(s)
Inhibidores de la Proteasa del VIH/análisis , Penicilinas/análisis , Secuencia de Aminoácidos , Línea Celular , Cromatografía Líquida de Alta Presión , Inhibidores de la Proteasa del VIH/farmacología , Cinética , Datos de Secuencia Molecular , Penicilinas/farmacología
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