RESUMEN
Tribbles pseudokinase-3 (TRIB3) has been proposed to act as an inhibitor of AKT although the precise molecular basis of this activity and whether the loss of TRIB3 contributes to cancer initiation and progression remain to be clarified. In this study, by using a wide array of in vitro and in vivo approaches, including a Trib3 knockout mouse, we demonstrate that TRIB3 has a tumor-suppressing role. We also find that the mechanism by which TRIB3 loss enhances tumorigenesis relies on the dysregulation of the phosphorylation of AKT by the mTORC2 complex, which leads to an enhanced phosphorylation of AKT on Ser473 and the subsequent hyperphosphorylation and inactivation of the transcription factor FOXO3. These observations support the notion that loss of TRIB3 is associated with a more aggressive phenotype in various types of tumors by enhancing the activity of the mTORC2/AKT/FOXO axis.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Factores de Transcripción Forkhead/metabolismo , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Humanos , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Noqueados , Ratones Desnudos , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Neoplasias/genética , Neoplasias/patología , Fosforilación/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Represoras/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
We investigated the prevalence of antiphospholipid antibodies (APA) in megakaryocytic thrombopenias in order to establish their clinical significance and prognostic value. We studied 82 thrombopenic patients: 38 women and 44 men (age: 17-91 years). We assessed circulating lupus antibody (LA) through thromboplastin inhibition test (TIT), anticardiolipin antibodies (ACL) through ELISA and antiplatelet antibodies through flow cytometer. We conducted a statistical study RSIGMA, comparing patients with ACL + against ACL-. We found ACL positive in 21%, LA in 33% and antiplatelet antibodies in 42%. We observed a direct correlation (p < 0.05) between ACL and LA and between ACL and anticore antibodies, but not between ACL and antiplatelet antibodies. There was also a significant correlation between ACL and abortion, thrombosis and bleeding in thrombopenic patients. We conclude that APAs are present in 39% of the megakaryocytic thrombopenias and that they are not correlated with antiplatelet antibodies. Positivity of APA in thrombopenic patients is associated to poor prognosis and long term follow-up.
Asunto(s)
Anticuerpos Antifosfolípidos/sangre , Megacariocitos/inmunología , Trombocitopenia/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/clasificación , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , España/epidemiología , Trombocitopenia/clasificación , Trombocitopenia/epidemiología , Trombocitopenia/etiologíaRESUMEN
Formation and evolution of calcium phosphates are investigated, at 37 degrees C, in urine and aqueous solutions whose concentrations in calcium and magnesium are close to those of urine. Although the solutions are supersaturated with respect to all calcium phosphates, only an amorphous phase (ACP) and brushite (B) precipitate at time zero. Later on, ACP transforms either into whitlockite (W) or into apatite (HAP) depending on the solution composition. Phase transformations are discussed in terms of supersaturation, parameter which includes concentrations and pH. It is also shown that magnesium is a powerful inhibitor of the evolution towards HAP.