RESUMEN
p73 is a transcription factor belonging to the p53 tumour suppressor family. p73-/- mice exhibit a range of phenotypes including neurological, reproductive and inflammatory defects. Although the role of p73 in the control of genomic stability explains part of these phenotypes, a clear mechanism of how p73 participates in the inflammatory response is still elusive. Interleukin-1ß (IL-1ß) has a crucial role in mediating the inflammatory response. Because of its high potency to induce inflammation, the activation and secretion of IL-1ß is tightly regulated by large protein complexes, named inflammasomes. Inflammasomes regulate activation of proinflammatory caspase-1, which in turn proteolytically processes its substrates, including pro-IL-1ß. Caspase-1 gene transcription is strongly activated by p53 protein family members including p73. Here, we have addressed whether p73 might be directly involved in IL-1ß regulation and therefore in the control of the inflammatory response. Our results show that TAp73ß upregulates pro-IL-1ß mRNA and processed IL-1ß protein. In addition, analysis of breast and lung cancer patient cohorts demonstrated that interaction between p73 and IL-1ß predicts a negative survival outcome in these human cancers.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteína Tumoral p73/metabolismo , Animales , Biomarcadores de Tumor/genética , Caspasa 1/metabolismo , Línea Celular Tumoral , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Inflamasomas/metabolismo , Ratones , Ratones Noqueados , Pronóstico , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Proteína Tumoral p73/antagonistas & inhibidores , Proteína Tumoral p73/deficiencia , Proteína Tumoral p73/genética , Regulación hacia ArribaRESUMEN
The transcription factor p73 has been demonstrated to play a significant role in survival and differentiation of neuronal stem cells. In this report, by employing comprehensive metabolic profile and mitochondrial bioenergetics analysis, we have explored the metabolic alterations in cortical neurons isolated from p73 N-terminal isoform specific knockout animals. We found that loss of the TAp73 or ΔNp73 triggers selective biochemical changes. In particular, p73 isoforms regulate sphingolipid and phospholipid biochemical pathway signaling. Indeed, sphinganine and sphingosine levels were reduced in p73-depleted cortical neurons, and decreased levels of several membrane phospholipids were also observed. Moreover, in line with the complexity associated with p73 functions, loss of the TAp73 seems to increase glycolysis, whereas on the contrary, loss of ΔNp73 isoform reduces glucose metabolism, indicating an isoform-specific differential effect on glycolysis. These changes in glycolytic flux were not reflected by parallel alterations of mitochondrial respiration, as only a slight increase of mitochondrial maximal respiration was observed in p73-depleted cortical neurons. Overall, our findings reinforce the key role of p73 in regulating cellular metabolism and point out that p73 exerts its functions in neuronal biology at least partially through the regulation of metabolic pathways.