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1.
PLoS One ; 10(6): e0131940, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26121334

RESUMEN

OBJECTIVE: Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity). METHODS AND RESULTS: PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 µM PFT. CONCLUSIONS: Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis.


Asunto(s)
Hipertensión Pulmonar/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Benzotiazoles/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/genética , Hipertrofia Ventricular Derecha/metabolismo , Masculino , Monocrotalina/toxicidad , Ratas , Ratas Wistar , Tolueno/análogos & derivados , Tolueno/farmacología , Proteína p53 Supresora de Tumor/genética
2.
Horm Metab Res ; 42(7): 514-20, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20379950

RESUMEN

Estrogens are known to stimulate the proliferation of human preadipocytes. However, the molecular mechanisms underlying the increased cell growth by these steroids are poorly understood. In the present study, we have demonstrated that the proliferative effect of 17beta-estradiol involves the induction of both cell cycle gene expressions, c-myc and cyclin D1. Moreover, the mitogenic effects of 17beta-estradiol are suppressed by the pure antagonist ICI 182780 suggesting that estradiol action is mediated by estrogen receptor (ER). We have also shown that 17beta-estradiol is able to inhibit human preadipocyte apoptosis capacity as reflected by DNA fragmentation experiments and the mRNA expression of the pro- and antiapoptotic genes. Finally, 17beta-estradiol significantly induces both mRNA and protein expression of RIGF1 in human preadipose cells via ER and thus reinforces the signaling pathway of the proliferative factor, IGF1. Taken together, these data reinforce the concept of cross-talk between IGF1- and ER-signaling pathways in preadipocytes and indicate that IGFI may be a critical regulator of estrogen-mediated preadipose growth.


Asunto(s)
Tejido Adiposo/citología , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Estrógenos/farmacología , Receptores de Somatomedina/metabolismo , Transducción de Señal/efectos de los fármacos , Adipocitos/citología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Adulto , Anciano , Células Cultivadas , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Persona de Mediana Edad , Receptores de Somatomedina/genética
3.
Dev Dyn ; 235(8): 2083-94, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16786588

RESUMEN

Elimination of tadpole organs during Xenopus metamorphosis is largely achieved through apoptosis, and recent evidence suggest involvement of the mitochondrial death route and bax-initiated caspase-3 and -9 deployment. However, events upstream of the activation of Bax are unknown. In other models, proteins of the BH3-only group such as BID are known to assure this function. We show that Xenopus bid transcript levels increase at metamorphosis in larval cells destined to disappear. This increase correlates with an abrupt rise in Caspase-2 and -8 mRNA levels and an enhanced activity of Caspase-2 and -8. In BIDGFP transgenic animal's tail regression is accelerated. The cleavage of BIDGFP fusion protein during natural or T(3)-induced metamorphosis was specifically inhibited by caspase-8 inhibitors. Our results show that tail regression at metamorphosis implicates an apoptotic pathway inducible by T(3) hormone in an organ autonomous manner and involving the cell death executioners BID and Caspases-2 and -8.


Asunto(s)
Apoptosis , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/metabolismo , Caspasas/metabolismo , Metamorfosis Biológica , Xenopus laevis/crecimiento & desarrollo , Xenopus laevis/metabolismo , Animales , Animales Modificados Genéticamente , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/clasificación , Proteína Proapoptótica que Interacciona Mediante Dominios BH3/genética , Caspasa 2 , Caspasa 8 , Inhibidores de Caspasas , Caspasas/genética , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros/genética , Larva/citología , Larva/crecimiento & desarrollo , Larva/metabolismo , Mitocondrias/metabolismo , Receptores de Superficie Celular/metabolismo , Cola (estructura animal)/citología , Cola (estructura animal)/efectos de los fármacos , Cola (estructura animal)/crecimiento & desarrollo , Cola (estructura animal)/metabolismo , Xenopus laevis/genética , Proteína bcl-X/metabolismo
5.
Mech Ageing Dev ; 122(2): 205-17, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11166359

RESUMEN

Some filamentous fungi exhibit a limited vegetative growth with modifications in the mitochondria, suggesting the involvement of mitochondria in the process of ageing. Nevertheless, the relationship between the ability to grow or the fate of these cells relative to their mitochondrial membrane potential (Psi(mt)) level has not been investigated. Using flow cytometric analysis, we have assessed Psi(mt) in young and senescent cultures of wild type strains and mitochondrial or nuclear mutant strains of Podospora anserina that present very long or brief life span. When we compared two distinct populations of cells obtained from the same strain, we can show a correlation not only between Psi(mt) and ageing, but also between Psi(mt) and the frequency of regeneration and/or the life span. However, this relationship is not observed when we compared the cells obtained from different physiological states or mutants strains. These results allow us to suggest that the Psi(mt) modifications during senescence could be only one of the possible consequences of the process and are not the factor driving towards death. We also show that the driving force of Psi(mt) is principally maintained by the alternative pathway during ageing, suggesting a role of the alternative oxidase pathway.


Asunto(s)
Mitocondrias/metabolismo , Sordariales/metabolismo , Carbocianinas , Colorantes Fluorescentes , Potenciales de la Membrana , Mutación , Protoplastos/metabolismo , Sordariales/genética , Sordariales/crecimiento & desarrollo , Factores de Tiempo
6.
Proc Natl Acad Sci U S A ; 97(8): 4138-43, 2000 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-10759557

RESUMEN

Senescence, a progressive degenerative process leading to age-related increase in mortality, is found in most eukaryotes. However, the molecular events underlying aging remain largely unknown. Understanding how longevity is regulated is a fundamental problem. Here we demonstrate that the respiratory function is a key factor that contributes to shortening lifespan of the filamentous fungus Podospora anserina. In this organism, senescence is systematically associated with mitochondrial DNA instabilities. We show that inactivation of the nuclear COX5 gene encoding subunit V of the cytochrome c oxidase complex leads to the exclusive use of the alternative respiratory pathway and to a decrease in production of reactive oxygen species. This inactivation results in a striking increase of longevity associated with stabilization of the mitochondrial chromosome. Moreover, accumulation of several senescence-specific mitochondrial DNA molecules is prevented in this nuclear mutant. These findings provide direct evidence of a causal link between mitochondrial metabolism and longevity in Podospora anserina.


Asunto(s)
Complejo IV de Transporte de Electrones/genética , Sordariales/fisiología , Secuencia de Bases , Cromosomas Fúngicos , Cartilla de ADN , Mitocondrias/genética , Datos de Secuencia Molecular , Fenotipo , Sordariales/genética
7.
FEBS Lett ; 460(2): 203-6, 1999 Oct 29.
Artículo en Inglés | MEDLINE | ID: mdl-10544235

RESUMEN

The REtsAF cell line expresses a temperature-sensitive mutant of the SV40 large tumor antigen. At restrictive temperature (39.5 degrees C), the cells undergo p53-mediated apoptosis, which can be inhibited by Bcl-2. Here, we show that Z-VAD-fmk, a caspase inhibitor, can suppress the Bcl-2-dependent cell survival at 39.5 degrees C. This result suggests that a caspase-like activity can act as an inhibitor of apoptosis in this model, downstream of Bcl-2. Our results also suggest that this activity may be up-regulated by Bcl-2 and may be responsible for cleavage of the tumor suppressor Rb protein.


Asunto(s)
Apoptosis , Inhibidores de Caspasas , Supervivencia Celular/efectos de los fármacos , Genes bcl-2/efectos de los fármacos , Clorometilcetonas de Aminoácidos/farmacología , Animales , Western Blotting , Línea Celular , Inhibidores de Cisteína Proteinasa/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Fibroblastos/metabolismo , Oligopéptidos/farmacología , Ratas , Transducción de Señal , Estaurosporina/farmacología , Temperatura , Tetraciclina/farmacología , Factores de Tiempo
8.
Oncogene ; 17(13): 1639-51, 1998 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-9796693

RESUMEN

Apoptosis, the process whereby cells activate an intrinsic death program, can be induced in HeLa cells by TNF-alpha treatment. The aims of the present study were (i) to examine the precise role and the origin of Reactive Oxygen Species (ROS) in the TNF-alpha-induced programmed cell death, (ii) to characterize and order the morphological and mitochondrial changes associated with this process and (iii) to link these events with the activation of caspases. Analyses were performed on TNF-alpha-treated cells in the presence of an anti-oxidant, or of a general caspase inhibitor. To assess the role of mitochondria in the cell death signal transduction, these studies were also realized on HeLa-variant cell lines lacking functional mitochondrial respiratory chain. We show that at least two separate signaling cascades, both mediated by Z-VAD-sensitive caspase(s), contribute to the TNF-alpha-induced apoptosis of HeLa cells. One signaling pathway involves an early mitochondria-dependent ROS production, the other being ROS-independent.


Asunto(s)
Apoptosis , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Clorometilcetonas de Aminoácidos/farmacología , Inhibidores de Cisteína Proteinasa/farmacología , Proteínas de Unión al GTP/fisiología , Células HeLa , Humanos , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Proteínas de Unión al GTP rho
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