Foo Roger S-Y, Nam Young-Jae, Ostreicher Marc Jason, Metzl Mark D, Whelan Russell S, Peng Chang-Fu, Ashton Anthony W, Fu Weimin, Mani Kartik, Chin Suet-Feung, Provenzano Elena, Ellis Ian, Figg Nichola, Pinder Sarah, Bennett Martin R, Caldas Carlos, Kitsis Richard N
Departments of Medicine and Cell Biology, Cardiovascular Research Center, and Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20826-31. doi: 10.1073/pnas.0710017104. Epub 2007 Dec 17.
Inactivation of the transcription factor p53 is central to carcinogenesis. Yet only approximately one-half of cancers have p53 loss-of-function mutations. Here, we demonstrate a mechanism for p53 inactivation by apoptosis repressor with caspase recruitment domain (ARC), a protein induced in multiple cancer cells. The direct binding in the nucleus of ARC to the p53 tetramerization domain inhibits p53 tetramerization. This exposes a nuclear export signal in p53, triggering Crm1-dependent relocation of p53 to the cytoplasm. Knockdown of endogenous ARC in breast cancer cells results in spontaneous tetramerization of endogenous p53, accumulation of p53 in the nucleus, and activation of endogenous p53 target genes. In primary human breast cancers with nuclear ARC, p53 is almost always WT. Conversely, nearly all breast cancers with mutant p53 lack nuclear ARC. We conclude that nuclear ARC is induced in cancer cells and negatively regulates p53.
转录因子p53的失活是致癌作用的核心。然而，只有大约一半的癌症具有p53功能丧失突变。在此，我们证明了一种由含半胱天冬酶募集结构域的凋亡抑制因子（ARC）使p53失活的机制，ARC是一种在多种癌细胞中诱导产生的蛋白质。ARC在细胞核中与p53四聚化结构域直接结合，抑制p53四聚化。这暴露了p53中的一个核输出信号，触发p53依赖于Crm1的转运至细胞质。敲低乳腺癌细胞中的内源性ARC会导致内源性p53自发四聚化、p53在细胞核中积累以及内源性p53靶基因的激活。在具有细胞核ARC的原发性人类乳腺癌中，p53几乎总是野生型。相反，几乎所有具有突变型p53的乳腺癌都缺乏细胞核ARC。我们得出结论，细胞核ARC在癌细胞中被诱导并对p53起负调控作用。
