Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence.
Recent studies have implicated interferon signaling in the regulation of cellular senescence. However, the role of specific interferon-inducible proteins in cellular senescence remains to be defined. Here we report that IFI 16, an interferon-inducible transcriptional modulator from the p200-protein family, contributes to cellular senescence of prostate epithelial cells. Normal human prostate epithelial cells (PrEC) in culture expressed detectable levels of IFI 16, and the levels increased more than fourfold when cells approached cellular senescence. Consistent with a role of IFI 16 in cellular senescence, human prostate cancer cell lines either did not express IFI 16 or expressed a variant form, which was primarily detected in the cytoplasm of prostate cancer cells and not in the nucleus. Moreover, overexpression of functional IFI 16 in human prostate cancer cell lines inhibited colony formation. Additionally, ectopic expression of IFI 16 in clonal prostate cancer cell lines was associated with a senescence-like phenotype, production of senescence-associated beta-galactosidase (a biochemical marker for cellular senescence), and reduction of S-phase cells in culture. Importantly, upregulation of p21WAF1 and inhibition of E2F-stimulated transcription accompanied inhibition of cell growth by IFI 16 in prostate cancer cell lines. Collectively, our observations support the idea that increased levels of IFI 16 in PrECs contribute to senescence-associated irreversible cell growth arrest.
Xin
Hong
H
Departments of Pathology and Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, 2160 South First Avenue, Mail code: 114B, Maywood, IL 60153, USA.
Curry
Jonathan
J
Johnstone
Ricky W
RW
Nickoloff
Brian J
BJ
Choubey
Divaker
D
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000378:metabolism; D048429:Cell Size; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000502:physiology; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003114:Colony-Forming Units Assay; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004847:Epithelial Cells / Q000378:metabolism; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D019942:Genes, p16; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000166:cytology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019892:eIF-2 Kinase / Q000096:biosynthesis / Q000235:genetics
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C076700:IFI16 protein, human; D007371:Interferon-gamma; D008156:Luciferases; D019892:eIF-2 Kinase