Sznarkowska Alicja, Olszewski Robert, Zawacka-Pankau Joanna
Katedra Biotechnologii, Pracownia Diagnostyki Molekularnej, Międzyuczelniany Wydział Biotechnologii, Uniwersytetu Gdańskiego i Gdańskiego Uniwersytetu Medycznego, 80-822 Gdańsk.
Postepy Hig Med Dosw (Online). 2010 Aug 20;64:396-407.
A powerful tumor suppressor--p53 protein is a transcription factor which plays a critical role in eliciting cellular responses to a variety of stress signals, including DNA damage, hypoxia and aberrant proliferative signals, such as oncogene activation. Since its discovery thirty one years ago, p53 has been connected to tumorigenesis as it accumulates in the transformed tumor cells. Cellular stress induces stabilization of p53 and promotes, depending on the stress level, cell cycle arrest or apoptosis in the irreversibly damaged cells. The p53 protein is found inactive in more than 50% of human tumors either by enhanced proteasomal degradation or due to the inactivating point mutations in its gene. Numerous data indicate that low molecular weight compounds, identified by molecular modeling or in the functional, cell-based assays, efficiently activate non-mutated p53 in cancer cells which in consequence leads to their elimination due to p53-dependent apoptosis. In this work we describe the structure and cellular function of p53 as well as the latest discoveries on the compounds with high anti-tumor activities aiming at reactivation of the tumor suppressor function of p53.
一种强大的肿瘤抑制因子——p53蛋白是一种转录因子，在引发细胞对多种应激信号的反应中起关键作用，这些应激信号包括DNA损伤、缺氧以及异常增殖信号，如癌基因激活。自31年前被发现以来，p53因在转化的肿瘤细胞中积累而与肿瘤发生相关联。细胞应激会诱导p53稳定，并根据应激水平促进细胞周期停滞或使不可逆受损细胞发生凋亡。在超过50%的人类肿瘤中，p53蛋白通过蛋白酶体降解增强或其基因中的失活点突变而处于失活状态。大量数据表明，通过分子建模或基于细胞的功能分析鉴定出的低分子量化合物能够有效激活癌细胞中未发生突变的p53，进而由于p53依赖的凋亡导致癌细胞被清除。在这项工作中，我们描述了p53的结构和细胞功能，以及关于具有高抗肿瘤活性的化合物的最新发现，这些化合物旨在重新激活p53的肿瘤抑制功能。
