title: ING1 induces apoptosis through direct effects at the mitochondria.
abstract: The ING family of tumor suppressors acts as readers and writers of the histone epigenetic code, affecting DNA repair, chromatin remodeling, cellular senescence, cell cycle regulation and apoptosis. The best characterized member of the ING family, ING1,interacts with the proliferating cell nuclear antigen (PCNA) in a UV-inducible manner. ING1 also interacts with members of the14-3-3 family leading to its cytoplasmic relocalization. Overexpression of ING1 enhances expression of the Bax gene and was reported to alter mitochondrial membrane potential in a p53-dependent manner. Here we show that ING1 translocates to the mitochondria of primary fibroblasts and established epithelial cell lines in response to apoptosis inducing stimuli, independent of the cellular p53 status. The ability of ING1 to induce apoptosis in various breast cancer cell lines correlates well with its degree of translocation to the mitochondria after UV treatment. Endogenous ING1 protein specifically interacts with the pro-apoptotic BCL2 family member BAX, and colocalizes with BAX in a UV-inducible manner. Ectopic expression of a mitochondria-targeted ING1 construct is more proficient in inducing apoptosis than the wild type ING1 protein. Bioinformatic analysis of the yeast interactome indicates that yeast ING proteins interact with 64 mitochondrial proteins. Also, sequence analysis of ING1 reveals the presence of a BH3-like domain. These data suggest a model in which stress-induced cytoplasmic relocalization of ING1 by14-3-3 induces ING1-BAX interaction to promote mitochondrial membrane permeability and represent a paradigm shift in our understanding of ING1 function in the cytoplasm and its contribution to apoptosis [corrected].
authors.affiliation: Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Bose
authors.forename: S
authors.initials: S
authors.lastname: Thakur
authors.forename: S
authors.initials: S
authors.lastname: Thalappilly
authors.forename: B Y
authors.initials: BY
authors.lastname: Ahn
authors.forename: S
authors.initials: S
authors.lastname: Satpathy
authors.forename: X
authors.initials: X
authors.lastname: Feng
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: S W
authors.initials: SW
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Riabowol
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D057809:HEK293 Cells; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D024101:Mitochondrial Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000528:radiation effects; D021381:Protein Transport / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D013312:Stress, Physiological / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein