Tumor Suppression Group

Madrid, Spain

Tumor Suppression Group

Madrid, Spain
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Lopez-Otin C.,University of Oviedo | Blasco M.A.,Telomeres and Telomerase Group | Partridge L.,Max Planck Institute for Biology of Ageing | Partridge L.,University College London | And 4 more authors.
Cell | Year: 2013

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. © 2013 Elsevier Inc.


Munoz-Espin D.,Tumor Suppression Group | Canamero M.,Histopathology Unit | Maraver A.,Tumor Suppression Group | Gomez-Lopez G.,Bioinformatics Unit | And 12 more authors.
Cell | Year: 2013

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence. © 2013 Elsevier Inc.


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.


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.


Herranz D.,Tumor Suppression Group | Munoz-Martin M.,Tumor Suppression Group | Canamero M.,Comparative Pathology Unit | Mulero F.,Molecular Imaging Unit | And 3 more authors.
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 p16Ink4a, 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.


Palacios J.A.,Telomeres and Telomerase Group | Herranz D.,Tumor Suppression Group | De Bonis M.L.,Telomeres and Telomerase Group | De Bonis M.L.,Instituto Of Ricovero E Cura A Carattere Scientifico | And 3 more authors.
Journal of Cell Biology | Year: 2010

Yeast Sir2 deacetylase is a component of the silent information regulator (SIR) complex encompassing Sir2/Sir3/Sir4. Sir2 is recruited to telomeres through Rap1, and this complex spreads into subtelomeric DNA via histone deacetylation. However, potential functions at telomeres for SIRT1, the mammalian orthologue of yeast Sir2, are less clear. We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1super) mouse models. Our results indicate that SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity. Using chromatin immunoprecipitation assays, we find that SIRT1 interacts with telomeric repeats in vivo. In addition, SIRT1 overexpression increases homologous recombination throughout the entire genome, including telomeres, centromeres, and chromosome arms. These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies. © 2010 Palacios et al.


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.


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.


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.


Llanos S.,Tumor Suppression Group | Serrano M.,Tumor Suppression Group
Cell Cycle | Year: 2010

Perturbation of ribosomal biogenesis has recently emerged as a relevant p53-activating pathway. This pathway can be initiated by depletion of certain ribosomal proteins, which is followed by the binding and inhibition of MDM2 by a different subset of ribosomal proteins that includes L11. Here, we report that depletion of L37 leads to cell cycle arrest in a L11- and p53-dependent manner. DNA damage can initiate ribosomal stress, although little is known about the mechanisms involved. We have found that some genotoxic insults, namely, UV light and cisplatin, lead to proteasomal degradation of L37 in the nucleoplasm and to the ensuing L11-dependent stabilization of p53. Moreover, ectopic L37 overexpression can attenuate the DNA damage response mediated by p53. These results support the concept that DNA damage-induced proteasomal degradation of L37 constitutes a mechanistic link between DNA damage and the ribosomal stress pathway, and is a relevant contributing signaling pathway for the activation of p53 in response to DNA damage. © 2010 Landes Bioscience.

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