Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma
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Animals
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Breast Neoplasms
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COS Cells
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Carcinoma, Non-Small-Cell Lung
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Cloning, Molecular
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Colorectal Neoplasms
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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DNA Damage / physiology
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Fibroblasts / cytology
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Gene Expression Regulation, Neoplastic
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Humans
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In Situ Nick-End Labeling
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Lung Neoplasms
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Mitochondria / metabolism
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Molecular Sequence Data
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Mutagenesis / physiology
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Osteosarcoma
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Phosphorylation
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Protein Binding / physiology
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Proteins / genetics*
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Proteins / metabolism*
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Serine / metabolism
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Signal Transduction / genetics
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Skin / cytology
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Transcriptional Activation / physiology
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Apoptosis Regulatory Proteins
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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P53AIP1 protein, human
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Proteins
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Tumor Suppressor Protein p53
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Serine
Associated data
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GENBANK/AB045830
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GENBANK/AB045831
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GENBANK/AB045832