Hupp T R
Dundee Cancer Research Institute, Department of Molecular Oncology, University of Dundee, Scotland, UK.
Cell Mol Life Sci. 1999 Jan;55(1):88-95. doi: 10.1007/s000180050272.
The tumour suppressor protein p53 is a stress-activated transcription factor whose activity is required for regulating the cellular response to stress and damage. The biochemical activity of p53 as a transcription factor can be regulated by partner proteins affecting stability, nuclear transport, signalling pathways modulating phosphorylation and interactions with components of the transcriptional machinery. The key structural determinants of p53 protein that drive sequence-specific DNA binding include the core specific DNA-binding domain and the tetramerization domain. Flanking these domains are more evolutionarily divergent carboxy- and amino-terminal regulatory motifs that further modulate tetramerization and sequence-specific transactivation. This review will mainly focus on the mechanisms whereby the tetramerization domain modulates sequence-specific DNA binding and how missense point mutations in p53 protein and the activity of molecular chaperones may lead to unfolding of mutant p53 tetramers in human tumours.
肿瘤抑制蛋白p53是一种应激激活的转录因子，其活性对于调节细胞对应激和损伤的反应是必需的。p53作为转录因子的生化活性可由影响稳定性、核转运、调节磷酸化的信号通路以及与转录机制成分相互作用的伴侣蛋白来调节。驱动序列特异性DNA结合的p53蛋白的关键结构决定因素包括核心特异性DNA结合结构域和四聚化结构域。在这些结构域两侧是进化上更具差异的羧基末端和氨基末端调节基序，它们进一步调节四聚化和序列特异性反式激活。本综述将主要关注四聚化结构域调节序列特异性DNA结合的机制，以及p53蛋白中的错义点突变和分子伴侣的活性如何导致人类肿瘤中突变p53四聚体的解折叠。
