p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53.
Through direct cloning of p53 binding sequences from human genomic DNA, we have isolated a novel gene, designated p53AIP1 (p53-regulated Apoptosis-Inducing Protein 1), whose expression is inducible by wild-type p53. Ectopically expressed p53AIP1, which is localized within mitochondria, leads to apoptotic cell death through dissipation of mitochondrial A(psi)m. We have found that upon severe DNA damage, Ser-46 on p53 is phosphorylated and apoptosis is induced. In addition, substitution of Ser-46 inhibits the ability of p53 to induce apoptosis and selectively blocks expression of p53AIP1. Our results suggest that p53AIP1 is likely to play an important role in mediating p53-dependent apoptosis, and phosphorylation of Ser-46 regulates the transcriptional activation of this apoptosis-inducing gene.
Oda
K
K
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Japan.
Arakawa
H
H
Tanaka
T
T
Matsuda
K
K
Tanikawa
C
C
Mori
T
T
Nishimori
H
H
Tamai
K
K
Tokino
T
T
Nakamura
Y
Y
Taya
Y
Y
D000230:Adenocarcinoma; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung; D003001:Cloning, Molecular; D015179:Colorectal Neoplasms; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004249:DNA Damage / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000502:physiology; D012516:Osteosarcoma; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D012867:Skin / Q000166:cytology; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C414742:P53AIP1 protein, human; D011506:Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine