ING1 isoforms differentially affect apoptosis in a cell age-dependent manner.
Recently, several novel human ING1 isoforms have been cloned. However,the biochemical functions and the involvement of these proteins in apoptosis remain uncharacterized. We have examined the apoptotic effects and biochemical functions of the two major human ING1 isoforms p47(ING1a) and p33(ING1b) in young and senescent human diploid fibroblasts induced to enter into apoptosis by diverse treatments. We have found that ING1 displayed isoform-, stimulus- and cell age-dependent apoptotic properties. We present evidence indicating that ING1 proteins bind to chromatin and are regulated in a manner related to their apoptotic properties. In agreement with previous reports, we have found that only young but not senescent fibroblasts were able to enter into apoptosis induced by growth factor deprivation. This effect was accompanied by up-regulation of endogenous p33(ING1b). Ectopic up-regulation of p33(ING1b), but not p47(ING1a), also induced apoptosis and sensitized young but not senescent cells to UV irradiation and hydrogen peroxide-mediated apoptosis. Cotransfection of p33(ING1b) and the tumor suppressor p53 increased the percentage of apoptotic cells yielded by either of these two proteins alone, in agreement with data from tumor cell models. Finally, we found that the chromatin binding affinity of p33(ING1b) was increased in senescent cells, which were resistant to apoptosis. Together, these data support the idea that the apoptotic functions of ING1 may be exerted by chromatin-related functions that are subject to cell age-dependent mechanisms of regulation.
Vieyra
Diego
D
Cancer Biology Research Group, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, T2N 4N1 Canada.
Toyama
Tatsuya
T
Hara
Yasuo
Y
Boland
Donna
D
Johnston
Randal
R
Riabowol
Karl
K
D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins; D016147:Genes, Tumor Suppressor; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation
D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins