Ing1 Mediates p53 Accumulation and Chromatin Modification in Response to Oncogenic Stress

• Published in: The Journal of biological chemistry 2007-10, Vol.282 (42), p.31060-31067
• Main Authors: Abad, María, Menéndez, Camino, Füchtbauer, Annette, Serrano, Manuel, Füchtbauer, Ernst-Martin, Palmero, Ignacio
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cellular Senescence - genetics; Chromatin Assembly and Disassembly - genetics; Embryo, Mammalian - metabolism; Embryo, Mammalian - pathology; Fibroblasts - metabolism; Fibroblasts - pathology; Heterochromatin - genetics; Heterochromatin - metabolism; Inhibitor of Growth Protein 1; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Knockout; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Quantitative Trait Loci - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M701639200

ING proteins are putative tumor suppressor proteins linked to the p53 pathway and to the chromatin modification machinery. Here we have analyzed the role of the products of the murine Ing1 locus in cellular tumor-protective responses, using mouse primary fibroblasts where the Ing1 locus has been inactivated by the integration of a βgeo cassette. We show that Ing1-deficient mouse embryonic fibroblasts display a defective senescence-like antiproliferative response against oncogenic Ras, affecting several senescence-specific markers. This phenotype is accompanied by a reduced accumulation of p53, which can be explained by the reduced basal p53 protein stability in the Ing1-deficient background. Ing1 deficiency also results in defects in the appearance of heterochromatic marks upon expression of oncogenic Ras, suggestive of impaired heterochromatin formation during oncogene-induced senescence. Our results support an important role for the Ing1 locus in protection against oncogenic stress in vivo, both as a mediator of p53 activation and as a regulator of chromatin remodeling processes.