VIB–K.U.Leuven, Department of Molecular and Developmental Genetics, Laboratory for Molecular Cancer Biology, Leuven, Belgium.
Curr Top Dev Biol. 2011;94:45-75. doi: 10.1016/B978-0-12-380916-2.00003-6.
The p53 tumor suppressor pathway is active in cells that are subjected to stress and/or damaged, where it promotes cell cycle arrest or apoptosis. In contrast, in normal cells that are not exposed to stress signals and in tumor cells p53 is tightly kept in check or completely silenced. In most, if not all, tumor cells p53 is indeed inactivated by mutations in the p53 locus or by alternative, yet unclear, mechanisms that impinge directly or indirectly on p53 function. Recent biochemical and genetic data indicate that tumor cells hijack and enforce some of the mechanisms used by normal cells to restrain p53 function. This is best illustrated by the aberrant expression in tumor cells of MDM2 and MDMX (or MDM4), two structurally related proteins that play a critical role in maintaining p53 in an OFF state under normal conditions, but in particular in embryonic and stem cells. These advances and their potential implications for the development of new cancer therapeutic strategies form the focus of this chapter.
p53 肿瘤抑制途径在受到应激和/或损伤的细胞中活跃，它促进细胞周期停滞或细胞凋亡。相比之下，在未暴露于应激信号的正常细胞中和肿瘤细胞中，p53 受到严格的控制或完全沉默。在大多数（如果不是全部）肿瘤细胞中，p53 确实因 p53 基因座的突变或通过直接或间接影响 p53 功能的其他尚不清楚的机制而失活。最近的生化和遗传数据表明，肿瘤细胞劫持并强制实施正常细胞用来抑制 p53 功能的一些机制。这一点在肿瘤细胞中异常表达 MDM2 和 MDMX（或 MDM4）两种结构相关蛋白中得到了最好的说明，这两种蛋白在正常条件下维持 p53 处于关闭状态，特别是在胚胎和干细胞中起着关键作用。这些进展及其对开发新的癌症治疗策略的潜在影响是本章的重点。
