RESUMEN
Monoubiquitination of core histone 2A (H2A-K119u) has a critical role in gene regulation in hematopoietic differentiation and other developmental processes. To explore the interplay of histone H2A deubiquitinase Myb-like SWIRM and MPN domain containing1 (2A-DUB/Mysm1) with the p53 axis in the sequential differentiation of mature lymphocytes from progenitors, we systematically analyzed hematopoiesis and early T-cell development using Mysm1(-/-) and p53(-/-)Mysm1(-/-) mice. Mysm1(-/-) thymi were severely hypoplastic with <10% of wild-type cell numbers as a result of a reduction of early thymocyte progenitors in context with defective hematopoietic stem cells, a partial block at the double-negative (DN)1-DN2 transition and increased apoptosis of double-positive thymocytes. Increased rates of apoptosis were also detected in other tissues affected by Mysm1 deficiency, including the developing brain and the skin. By quantitative PCR and chromatin immunoprecipitation analyses, we identified p19(ARF), an important regulator of p53 tumor suppressor protein levels, as a potential Mysm1 target gene. In newly generated p53(-/-)Mysm1(-/-) double-deficient mice, anomalies of Mysm1(-/-) mice including reduction of lymphoid-primed multipotent progenitors, reduced thymocyte numbers and viability, and interestingly defective B-cell development, growth retardation, neurological defects, skin atrophy, and tail malformation were almost completely restored as well, substantiating the involvement of the p53 pathway in the alterations caused by Mysm1 deficiency. In conclusion, this investigation uncovers a novel link between H2A deubiquitinase 2A-DUB/Mysm1 and suppression of p53-mediated apoptotic programs during early lymphoid development and other developmental processes.
Asunto(s)
Inhibidor p19 de las Quinasas Dependientes de la Ciclina/metabolismo , Endopeptidasas/metabolismo , Hematopoyesis/fisiología , Histonas/metabolismo , Linfocitos T/citología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Diferenciación Celular/fisiología , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/metabolismo , Transactivadores , Proteasas Ubiquitina-EspecíficasRESUMEN
Rosacea fulminans (also known as pyoderma faciale) has been reported to occur in association with Crohn's disease. It is still unclear whether the papulopustules and confluent nodules of rosacea fulminans represent a manifestation of mucocutaneous Crohn's disease or whether this association is a mere coincidence. A 46-year-old woman presented with the spontaneous outbreak of rosacea fulminans and pyostomatitis/pyovulvitis. Complete remission of the mucocutaneous symptoms was achieved with 2 months combination therapy with methylprednisolone, isotretinoin and dapsone. The patient's Crohn's disease, already diagnosed for 3 years, did not flare during this period.
Asunto(s)
Enfermedad de Crohn/tratamiento farmacológico , Dapsona/administración & dosificación , Isotretinoína/administración & dosificación , Metilprednisolona/administración & dosificación , Rosácea/tratamiento farmacológico , Estomatitis/tratamiento farmacológico , Vulvitis/tratamiento farmacológico , Antiinfecciosos/administración & dosificación , Antiinflamatorios/administración & dosificación , Enfermedad de Crohn/complicaciones , Fármacos Dermatológicos/administración & dosificación , Combinación de Medicamentos , Femenino , Humanos , Persona de Mediana Edad , Rosácea/complicaciones , Estomatitis/complicaciones , Resultado del Tratamiento , Vulvitis/complicacionesRESUMEN
R- cells are 3T3 cells derived from mouse embryos with a targeted disruption of the type 1 insulin-like growth factor receptor (IGF-IR) genes. R- cells are refractory to transformation by a variety of viral and cellular oncogenes, including an activated Ras. R- cells stably transfected with an activated Ha-Ras (R-Ras cells) fail to form colonies in soft agar. An IGF-IR truncated at residue 1245 cannot transform R- cells, even when strongly overexpressed. However, the combination of the truncated IGF-IR and an activated Ras induces transformation of R- cells. We show here that the Ras oncoprotein is rapidly degraded when R-Ras cells are grown under anchorage-independent conditions and that signaling from the truncated IGF-IR stabilizes Ras. In monolayer cultures, Ras levels remain constant regardless of the presence or absence of IGF-IR signaling. These results directly explain why Ras cannot transform mouse embryo fibroblasts devoid of IGF-IR. They also suggest a more generalized, alternative mechanism for transformation by Ras and, implicitly, another possible way for targeting Ras in tumor cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular , Receptor IGF Tipo 1/fisiología , Transformación Genética/fisiología , Proteínas ras/fisiología , Células 3T3/fisiología , Animales , Adhesión Celular/fisiología , División Celular/fisiología , Células Cultivadas , Regulación hacia Abajo , Humanos , Proteínas Sustrato del Receptor de Insulina , Ratones , Fosfoproteínas/fisiología , Fosforilación , Polihidroxietil Metacrilato , Proteínas/metabolismo , Receptor IGF Tipo 1/genética , Proteínas Adaptadoras de la Señalización Shc , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src , Proteínas ras/metabolismoRESUMEN
Conscious dogs were used to study whether changes in total renal hemodynamics are responsible for diuresis and natriuresis during an experimental increase in left atrial pressure (LAP). To ensure a controlled dietary sodium intake, the dogs (n = 8) were chronically kept on a high or a low sodium intake diet (HSI; LSI). After the dogs had completely recovered from surgery (carotid loop, thoracotomy, flank incision), LAP was increased by about 10 cm H2O for 60 min by tightening a purse string around the mitral annulus (51 expts.). Mean urine volume (V) increased in both groups to a comparable degree. Mean sodium excretion increased somewhat more in HSI dogs, but remained elevated in LSI dogs after the LAP increase. Renal blood flow (electromagnetic flow transducer) and inulin clearance did not change. Renal vascular resistance (RVR) increased by about 20% (HSI) and 15% (LSI). --When the induced LAP INCREASE WAS TERMINATED, V decreased. RVR decreased in HSI dogs by about -11% and in LSI dogs by about -6% below control values. --It is concluded that volume regulatory mechanisms induced by an experimental LAP increase operate independently of changes in total renal blood flow.
Asunto(s)
Hipertensión/fisiopatología , Riñón/irrigación sanguínea , Natriuresis , Animales , Dieta , Perros , Femenino , Riñón/fisiopatología , Flujo Sanguíneo Regional , Cloruro de Sodio/administración & dosificación , Factores de Tiempo , Resistencia VascularRESUMEN
5 conscious, well trained, female dogs kept on a high sodium intake (14 meq Na/kg bw) were used to measure left atrial pressure (LAP), urine volume (V), sodium and potassium excretion (UNaV, UKV) as well as plasma osmolality (Posm) before and up to 180 min after food intake. The dogs were fitted with a catheter in the left atrium (thoracotomy). In all experiments (n=23) LAP increased postprandially (pp) above fasting controls. The mean peak increase ranged from 4 to 6 cm H2O and was observed as early as 61-80 and as late as 161-180 min pp. Increase in LAP was closely correlated to V which rose from 36+28 to 160+51/ul/min. kg. pp V was also correlated to pp UNa V, which increased from 4.8 +/- 3.3 to 34.O+/-8.5/ueq/min-kg. The pp increase in LAP and its close relation to pp V and pp UNav emphasize the assumption that intrathoracic receptors are involved in the regulation of body fluids.
Asunto(s)
Función Atrial , Diuresis , Ingestión de Alimentos , Presorreceptores/fisiología , Sodio , Animales , Dieta , Perros , FemeninoRESUMEN
Postprandial renal blood flow was studied in 14 conscious dogs on a chronic high and low sodium intake on 72 days after implantation of an electromagnetic flow transducer around the left renal artery. Fasting renal blood flow was 11.7 plus or minus 3.2 ml/min with kg on high socium intake (43 days) and 11.5 plus or minus 3.3 ml/min with kg on low sodium intake (29 days). During ingestion no change of renal blood flow occurred; mean arterial pressure rose transiently. During digestion renal blood flow increased always and was, like the fasting renal blood flow of dogs on a high sodium intake was 41 plus or minus 23%, and of dogs on a low sodium intake 35 plus or minus 15% referring to fasting controls; peak increase mostly occurred between 60 and90 min postprandially and was due to a decrease of renal vascular resistance. Renal blood flow also increased after augmentation of intravascular volume by an intravenous infusion; volume receptors may be involved.