Requirement of IFI16 for the maximal activation of p53 induced by ionizing radiation.
IFI16 is a member of the PYRIN superfamily that has been implicated in BRCA1-mediated apoptosis and inflammation signaling pathways. Here we report that most breast cancer cell lines examined expressed decreased mRNA and protein levels of IFI16, although IFI16 is expressed in human primary normal mammary epithelial cells. Significantly, immunohistochemical analysis of tissues from 25 breast cancer patients demonstrated that carcinoma cells showed negative or weaker staining of IFI16 compared with positive nuclear staining in normal mammary duct epithelium. si-RNA-mediated reduction of IFI16 resulted in perturbation of p53 activation when treated with ionizing radiation (IR). Expression of IFI16 enhanced p53 transcriptional activity in cells exposed to IR. Adenovirus expression of IFI16 in IFI16-deficient MCF7 induced apoptosis, which was enhanced by radiomimetic neocarcinostatin treatment. Tetracycline-regulated IFI16 also induced apoptosis when coexpressed with p53 in p53-deficient EJ cells subjected to IR, suggesting that IFI16 is involved in p53-mediated transmission of apoptosis signaling. Consistent with these results, expression of IFI16 enhanced activation of the known p53 target genes, including p21, Hdm2, and bax in MCF7 cells. These results suggest that loss of IFI16 results in deregulation of p53-mediated apoptosis, leading to cancer development.
Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York University, One Gustave L. Levy Place, New York, NY 10029, USA.
Nobuko
N
Fujiuchi
Jason A
JA
Aglipay
Takao
T
Ohtsuka
Naoki
N
Maehara
Fikret
F
Sahin
Gloria H
GH
Su
Sam W
SW
Lee
Toru
T
Ouchi
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D019313:BRCA1 Protein / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction; D013752:Tetracycline / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D019313:BRCA1 Protein; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C076700:IFI16 protein, human; D012313:RNA; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D013752:Tetracycline