Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Japan.
Cell. 2000 Sep 15;102(6):849-62. doi: 10.1016/s0092-8674(00)00073-8.
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.
通过直接从人类基因组DNA中克隆p53结合序列，我们分离出了一个新基因，命名为p53AIP1（p53调控的凋亡诱导蛋白1），其表达可被野生型p53诱导。异位表达的p53AIP1定位于线粒体中，通过线粒体膜电位（Δψm）的消散导致凋亡性细胞死亡。我们发现，在严重DNA损伤时，p53上的Ser-46被磷酸化并诱导凋亡。此外，Ser-46的替代抑制了p53诱导凋亡的能力，并选择性地阻断了p53AIP1的表达。我们的结果表明，p53AIP1可能在介导p53依赖性凋亡中起重要作用，并且Ser-46的磷酸化调节了这个凋亡诱导基因的转录激活。
