4 research outputs found
ATM kinase dead: from ataxia telangiectasia syndrome to cancer
No full textATM is one of the principal players of the DNA damage response. This protein exerts its role in DNA repair during cell cycle replication, oxidative stress, and DNA damage from endogenous events or exogenous agents. When is activated, ATM phosphorylates multiple substrates that participate in DNA repair, through its phosphoinositide 3-kinase like domain at the 3'end of the protein. The absence of ATM is the cause of a rare autosomal recessive disorder called Ataxia Telangiectasia characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility, and radiation sensitivity. There is a correlation between the severity of the phenotype and the mutations, depending on the residual activity of the protein. The analysis of patient mutations and mouse models revealed that the presence of inactive ATM, named ATM kinase-dead, is more cancer prone and lethal than its absence. ATM mutations fall into the whole gene sequence, and it is very difficult to predict the resulting effects, except for some frequent mutations. In this regard, is necessary to characterize the mutated protein to assess if it is stable and maintains some residual kinase activity. Moreover, the whole-genome sequencing of cancer patients with somatic or germline mutations has highlighted a high percentage of ATM mutations in the phosphoinositide 3-kinase domain, mostly in cancer cells resistant to classical therapy. The relevant differences between the complete absence of ATM and the presence of the inactive form in in vitro and in vivo models need to be explored in more detail to predict cancer predisposition of A-T patients and to discover new therapies for ATM-associated cancer cells. In this review, we summarize the multiple discoveries from humans and mouse models on ATM mutations, focusing into the inactive versus null ATM
Glioblastoma Cells Do Not Affect Axitinib-Dependent Senescence of HUVECs in a Transwell Coculture Model
No full textAxitinib is an orally available inhibitor of tyrosine kinases, with high specificity for vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is approved for the treatment of advanced renal cell carcinoma and is in phase II clinical trials for recurrent glioblastoma (GBM). GBM is a brain tumor peculiar in its ability to induce neoangiogenesis. Since both GBM tumor cells and endothelial cells of tumor vasculature express VEGFRs, Axitinib exerts its inhibitory action on both tumor and endothelial cells. We and others previously demonstrated that Axitinib triggers cellular senescence. In particular, Axitinib-dependent senescence of HUVECs (human umbilical vein endothelial cells) is accompanied by intracellular reactive oxygen species(ROS) increase and early ataxia telangiectasia mutated(ATM) activation. Here we wondered if the presence of glioblastoma tumor cells could affect the HUVEC senescence upon Axitinib exposure. To address this issue, we cocultured HUVECs together with GBM tumor cells in transwell plates. HUVEC senescence did not result in being affected by GBM cells, neither in terms of β galactosidase activity nor of proliferation index or ATM phosphorylation. Conversely, Axitinib modulation of HUVEC gene expression was altered by cocultured GBM cells. These data demonstrate that the GBM secretome modifies HUVECs’ transcriptomic profile upon Axitinib exposure, but does not prevent drug-induced senescence
Hematopoietic stem/progenitor cell transplantation recovers immune defects and prevents lymphomas in Atm-deficient mice
No full textAbstract Background Ataxia-telangiectasia (A-T) is a rare autosomal recessive multi-system and life-shortening disease, characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition, with high incidence of leukemia and lymphoma. A-T is caused by mutations in the gene encoding for ATM protein that has a major role in maintaining the integrity of the genome. Because there are no cures for A-T, we aimed to tackle immunodeficiency and prevent cancer onset/progression by transplantation therapy. Methods Enriched hematopoietic stem/progenitor cells (HSPCs), collected from bone marrow of wild-type mice, were transplanted in the caudal vein of 1 month old conditioned Atm −/− mice. Results Genomic analyses showed that transplanted Atm positive cells were found in lymphoid organs. B cells isolated from spleen of transplanted mice were able to undergo class switching recombination. Thymocytes were capable to correctly differentiate and consequently an increase of helper T cells and TCRβhi expressing cells was observed. Protein analysis of isolated T and B cells from transplanted mice, revealed that they expressed Atm and responded to DNA damage by initiating an Atm-dependent phosphorylation cascade. Indeed, aberrant metaphases were reduced in transplanted Atm-deficient mice. Six months after transplantation, Atm −/− mice showed signs of aging, but they maintained the rescue of T cells maturation, showed DNA damage response, and prevented thymoma. Conclusion We can conclude that wild-type enriched HSPCs transplantation into young Atm-deficient mice can ameliorate A-T hematopoietic phenotypes and prevent tumor of hematopoietic origin
El cancionero musical (1599) de Antonio Gutiérrez. Un músico español de Nápoles al servicio del duque de Mantua
No full textDuring the first decades of the seventeenth century, Spanish vocal music had a significant presence in Italy and other European regions. The discovery of a volume dated 1599 containing original music by Antonio Gutiérrez, preserved in the library of the Correr Museum in Venice, allows us to considerably expand our understanding of the phenomenon of arie and villanelle. Its importance lies not only in the fact that it is written in mensural notation with guitar accompaniment in tablature, but also in its relationship to certain manuscript sources, as some of its 29 two-voice compositions, with notated music and guitar accompaniment, correspond with other Italian sources of poetry with alphabet. The discovery of this manuscript, dedicated by the author himself to the Duke of Mantua, allows us to approach the creators of this repertoire and question some assumptions about its provenance. This article aims to present this new source in its context and contribute to knowledge of its author’s figure, as well as to address some of the most relevant technical-stylistic aspects, as a preview of a critical edition of the music that is currently in preparation.Durante las primeras décadas del siglo XVII, la música vocal en español tuvo una presencia significativa en Italia y otras regiones europeas. El hallazgo de un volumen fechado en 1599 con música original de Antonio Gutiérrez, conservado en la biblioteca del Museo Correr de Venecia, permite ampliar considerablemente nuestra visión del cultivo de la canción en español en tierras transalpinas durante el nacimiento del barroco. Su importancia radica no sólo en el hecho de estar escrito en notación mensural, con acompañamiento de guitarra en tablatura, sino en la relación que guarda con ciertas fuentes manuscritas pues algunas de sus 29 composiciones a dos voces, con música notada y acompañamiento de guitarra, concuerdan con otras fuentes italianas de poesía con alfabeto. El descubrimiento de este manuscrito, dedicado por el propio autor al duque de Mantua, nos permite acercarnos a los artífices del repertorio, y cuestionar algunas asunciones acerca de su procedencia. Este artículo se propone dar noticia de esta nueva fuente en su contexto y contribuir al conocimiento de la figura de su autor, así como tratar algunos de los aspectos técnico-estilísticos más relevantes, como adelanto de una edición crítica de la música que está en proceso de preparación
