Chen L, Marechal V, Moreau J, Levine A J, Chen J
Department of Microbiology, Immunology, and Parasitology, Louisiana State University Medical Center, Stanley S. Scott Cancer Center, New Orleans, Louisiana 70112, USA.
J Biol Chem. 1997 Sep 5;272(36):22966-73. doi: 10.1074/jbc.272.36.22966.
The mdm2 oncogene encodes a 90-kDa protein that can bind to the p53 tumor suppressor protein and negatively regulate its functions in transcription, cell cycle arrest, and apoptosis. The mdm2 gene is frequently amplified in human sarcomas, which may be responsible for the malignant transformations. We present evidence that the mdm2 oncoprotein is cleaved by an interleukin 1beta-converting enzyme-like protease (caspase) during p53-mediated apoptosis. The protease that cleaves mdm2 has a specificity similar to that of CPP32 (caspase-3), and recombinant caspase-3 is able to cleave mdm2 in vitro. The protease cleavage site has been mapped to between residue 361 and 362 of human mdm2. The proteolytic cleavage removes the COOH-terminal RING finger domain of mdm2, resulting in the loss of RNA binding activity. The p53 binding and inhibition functions of mdm2 are not affected by the cleavage. The cleavage site sequence of mdm2 is evolutionarily conserved, suggesting that regulation by caspase cleavage during apoptosis is an important feature of mdm2.
mdm2癌基因编码一种90 kDa的蛋白质，它能与p53肿瘤抑制蛋白结合，并在转录、细胞周期停滞和凋亡过程中对其功能进行负调控。mdm2基因在人类肉瘤中经常扩增，这可能是恶性转化的原因。我们提供的证据表明，在p53介导的凋亡过程中，mdm2癌蛋白被一种白细胞介素1β转化酶样蛋白酶（半胱天冬酶）切割。切割mdm2的蛋白酶具有与CPP32（半胱天冬酶-3）相似的特异性，并且重组半胱天冬酶-3能够在体外切割mdm2。蛋白酶切割位点已定位到人类mdm2的第361和362位残基之间。蛋白水解切割去除了mdm2的COOH末端环指结构域，导致RNA结合活性丧失。mdm2的p53结合和抑制功能不受切割影响。mdm2的切割位点序列在进化上是保守的，这表明凋亡过程中半胱天冬酶切割调控是mdm2的一个重要特征。
