title: The tumor suppressor ING1 contributes to epigenetic control of cellular senescence.
abstract: Cellular senescence is an effective tumor-suppressive mechanism that causes a stable proliferative arrest in cells with potentially oncogenic alterations. Here, we have investigated the role of the p33ING1 tumor suppressor in the regulation of cellular senescence in human primary fibroblasts. We show that p33ING1 triggers a senescent phenotype in a p53-dependent fashion. Also, endogenous p33ING1 protein accumulates in chromatin in oncogene-senescent fibroblasts and its silencing by RNA interference impairs senescence triggered by oncogenes. Notably, the ability to induce senescence is lost in a mutant version of p33ING1 present in human tumors. Using specific point mutants, we further show that recognition of the chromatin mark H3K4me3 is essential for induction of senescence by p33ING1. Finally, we demonstrate that ING1-induced senescence is associated to a specific genetic signature with a strong representation of chemokine and cytokine signaling factors, which significantly overlaps with that of oncogene-induced senescence. In summary, our results identify ING1 as a critical epigenetic regulator of cellular senescence in human fibroblasts and highlight its role in control of gene expression in the context of this tumor-protective response.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, E-28029 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Abad
authors.forename: Alberto
authors.initials: A
authors.lastname: Moreno
authors.forename: Alicia
authors.initials: A
authors.lastname: Palacios
authors.forename: Masako
authors.initials: M
authors.lastname: Narita
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.forename: Masashi
authors.initials: M
authors.lastname: Narita
authors.forename: Ignacio
authors.initials: I
authors.lastname: Palmero
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D018929:Cell Culture Techniques; D016922:Cellular Senescence / Q000235:genetics*; D018925:Chemokines / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D057890:Epigenomics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005809:Genes, Regulator / Q000502:physiology; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018925:Chemokines; D002843:Chromatin; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins