Division of Cardiology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
J Biol Chem. 2011 Sep 16;286(37):32575-85. doi: 10.1074/jbc.M110.217836. Epub 2011 Jul 27.
Tumor suppressor protein p53, our most critical defense against tumorigenesis, can be made powerless by mechanisms such as mutations and inhibitors. Fortilin, a 172-amino acid polypeptide with potent anti-apoptotic activity, is up-regulated in many human malignancies. However, the exact mechanism by which fortilin exerts its anti-apoptotic activity remains unknown. Here we present significant insight. Fortilin binds specifically to the sequence-specific DNA binding domain of p53. The interaction of fortilin with p53 blocks p53-induced transcriptional activation of Bax. In addition, fortilin, but not a double point mutant of fortilin lacking p53 binding, inhibits p53-dependent apoptosis. Furthermore, cells with wild-type p53 and fortilin, but not cells with wild-type p53 and the double point mutant of fortilin lacking p53 binding, fail to induce Bax gene and apoptosis, leading to the formation of large tumor in athymic mice. Our results suggest that fortilin is a novel p53-interacting molecule and p53 inhibitor and that it is a logical molecular target in cancer therapy.
抑癌蛋白 p53 是我们对抗肿瘤生成的最重要防御机制，但它可以通过突变和抑制剂等机制而失效。Fortilin 是一种具有强大抗凋亡活性的 172 个氨基酸多肽，在许多人类恶性肿瘤中上调。然而，Fortilin 发挥其抗凋亡活性的确切机制尚不清楚。在这里，我们提供了重要的见解。Fortilin 特异性结合 p53 的序列特异性 DNA 结合域。Fortilin 与 p53 的相互作用阻止了 p53 诱导的 Bax 的转录激活。此外，Fortilin 但不是缺乏 p53 结合的 Fortilin 的双点突变体，抑制了 p53 依赖性细胞凋亡。此外，具有野生型 p53 和 Fortilin 的细胞，但不是具有野生型 p53 和缺乏 p53 结合的 Fortilin 的双点突变体的细胞，未能诱导 Bax 基因和细胞凋亡，导致无胸腺小鼠中形成大肿瘤。我们的结果表明，Fortilin 是一种新型的 p53 相互作用分子和 p53 抑制剂，是癌症治疗的合理分子靶标。
