Loss of p53-regulatory protein IFI16 induces NBS1 leading to activation of p53-mediated checkpoint by phosphorylation of p53 SER37.
Our previous results that IFI16 is involved in p53 transcription activity under conditions of ionizing radiation (IR), and that the protein is frequently lost in human breast cancer cell lines and breast adenocarcinoma tissues suggesting that IFI16 plays a crucial role in controlling cell growth. Here, we show that loss of IFI16 by RNA interference in cell culture causes elevated phosphorylation of p53 Ser37 and accumulated NBS1 (nibrin) and p21WAF1, leading to growth retardation. Consistent with these observations, doxycyclin-induced NBS1 caused accumulation of p21WAF1 and increased phosphorylation of p53 Ser37, leading to cell cycle arrest in G1 phase. Wortmannin treatment was found to decrease p53 Ser37 phosphorylation in NBS-induced cells. These results suggest that loss of IFI16 activates p53 checkpoint through NBS1-DNA-PKcs pathway.
Tawara
Hideyuki
H
Department of Oncological Sciences, The Mount Sinai School of Medicine, New York University, New York, NY, USA.
Fujiuchi
Nobuko
N
Sironi
Juan
J
Martin
Sarah
S
Aglipay
Jason
J
Ouchi
Mutsuko
M
Taga
Makoto
M
Chen
Phang-Lang
PL
Ouchi
Toru
T
D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics* / Q000502:physiology*; D010766:Phosphorylation; D011839:Radiation, Ionizing; D012694:Serine / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; C112156:NBN protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53; C076700:IFI16 protein, human; D012694:Serine