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Blasco M.A.,Telomeres and Telomerase Group | Serrano M.,Tumor Suppression Group | Fernandez-Capetillo O.,Genomic Instability Group
EMBO Journal | Year: 2011

The discovery of a simple protocol capable of generating pluripotent stem cells from terminally differentiated cells has been one of the most promising breakthroughs in recent biomedical research. Since their discovery, manuscripts characterizing properties of induced Pluripotent Stem (iPS) have flooded the literature. Among others, the analysis of the transcriptome and epigenome of iPS is now a recurrent theme that is helping to understand the molecular mechanisms behind reprogramming. Recent works have revealed that transcriptional and epigenetic reprogramming is often incomplete, which has raised some concerns on the nature of iPS. Inevitably, now the genome itself of iPS has been scrutinized; and the reports come with an unexpected twist: the presence of mutations in the genome of iPS. © 2011 European Molecular Biology Organization | All Rights Reserved. Source


Lopez-Mateo I.,Institute Investigaciones Biomedicas Alberto Sols | Villaronga M.A.,Hospital Universitario Central Of Asturias | Llanos S.,Tumor Suppression Group | Belandia B.,Institute Investigaciones Biomedicas Alberto Sols
Cell Cycle | Year: 2012

CREBZF is a member of the mammalian AtF/CREB family of transcription factors. Here, we describe a novel functional interaction between CReBZF and the tumor suppressor p53. CReBZF was identifed in a yeast two-hybrid screen using HEY1, recently characterized as an indirect p53 activator, as bait. CREBZF interacts in vitro with both HEY1 and p53, and CREBZF expression stabilizes and activates p53. Moreover, CREBZF cooperates synergistically with HEY1 to enhance p53 transcriptional activity. On the other hand, partial depletion of endogenous CReBZF diminishes p53 protein levels and inhibits HeY1-mediated activation of p53. CREBZF-positive efects on p53 signaling may refect, at least in part, an observed induction of posttranslational modifcations in p53 known to prevent its degradation. CREBZF expression protects HCT116 cells from UV radiation-induced cell death. In addition, CREBZF expression confers sensitivity to 5-fuorouracil, a p53-activating chemotherapeutic drug. Our study suggests that CREBZF may participate in the modulation of p53 tumor suppressor function. © 2012 Landes Bioscience. Source


Fernandez-Marcos P.J.,IMDEA Madrid Institute for Advanced Studies | Serrano M.,Tumor Suppression Group
Cell Metabolism | Year: 2016

Cellular senescence is a damage response characterized by a stable cell-cycle arrest and an intense secretion of cytokines. In this issue of Cell Metabolism, Wiley et al. (2016) report that, in the case of mitochondrial damage, senescence occurs with an atypical secretory phenotype, in both adipose tissue and skin. © 2016 Elsevier Inc. Source


Villaronga M.A.,Autonomous University of Madrid | Lavery D.N.,Imperial College London | Bevan C.L.,Imperial College London | Llanos S.,Tumor Suppression Group | Belandia B.,Autonomous University of Madrid
Oncogene | Year: 2010

The hairy/enhancer-of-split related with YRPW motif 1 (HEY1) is a member of the basic-helix-loop-helix-Orange (bHLH-O) family of transcriptional repressors that mediate Notch signaling. Several cancer-related pathways also regulate HEY1 expression, and HEY1 itself acts as an indirect positive regulator of the p53 tumor suppressor protein and a negative regulator of androgen receptor activity. In this study we show how a naturally occurring non-synonymous polymorphism at codon 94 of HEY1, which results in a substitution of leucine by methionine (Leu94Met), converts HEY1 from an androgen receptor corepressor to an androgen receptor co-activator without affecting its intrinsic transcriptional repressive domains. The polymorphism Leu94Met also abolishes HEY1-mediated activation of p53 and suppresses the ability of HEY1 to induce p53-dependent cell-cycle arrest and aberrant cell differentiation in human osteosarcoma U2OS cells. Moreover, expression of HEY1, but not of the variant Leu94Met, confers sensitivity to p53-activating chemotherapeutic drugs on U2OS cells. In addition, we have identified motifs in HEY1 that are critical for the regulation of its subcellular localization and analysed how mutations in those motifs affect both HEY1 and HEY1-Leu94Met functions. These findings suggest that the polymorphism Leu94Met in HEY1 radically alters its biological activities and may affect oncogenic processes. © 2010 Macmillan Publishers Limited All rights reserved. Source


Herranz D.,Tumor Suppression Group
Nature communications | Year: 2010

Genetic overexpression of protein deacetylase Sir2 increases longevity in a variety of lower organisms, and this has prompted interest in the effects of its closest mammalian homologue, Sirt1, on ageing and cancer. We have generated transgenic mice moderately overexpressing Sirt1 under its own regulatory elements (Sirt1-tg). Old Sirt1-tg mice present lower levels of DNA damage, decreased expression of the ageing-associated gene p16(Ink4a), a better general health and fewer spontaneous carcinomas and sarcomas. These effects, however, were not sufficiently potent to affect longevity. To further extend these observations, we developed a metabolic syndrome-associated liver cancer model in which wild-type mice develop multiple carcinomas. Sirt1-tg mice show a reduced susceptibility to liver cancer and exhibit improved hepatic protection from both DNA damage and metabolic damage. Together, these results provide direct proof of the anti-ageing activity of Sirt1 in mammals and of its tumour suppression activity in ageing- and metabolic syndrome-associated cancer. Source

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