Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, Texas 77030, USA.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Genes Dev. 2020 Sep 1;34(17-18):1128-1146. doi: 10.1101/gad.340976.120.
The p53 tumor suppressor functions as a tetrameric transcription factor to regulate hundreds of genes-many in a tissue-specific manner. Missense mutations in cancers in the p53 DNA-binding and tetramerization domains cement the importance of these domains in tumor suppression. p53 mutants with a functional tetramerization domain form mixed tetramers, which in some cases have dominant-negative effects (DNE) that inactivate wild-type p53. DNA damage appears necessary but not sufficient for DNE, indicating that upstream signals impact DNE. Posttranslational modifications and protein-protein interactions alter p53 tetramerization affecting transcription, stability, and localization. These regulatory components limit the dominant-negative effects of mutant p53 on wild-type p53 activity. A deeper understanding of the molecular basis for DNE may drive development of drugs that release WT p53 and allow tumor suppression.
p53 肿瘤抑制因子作为四聚体转录因子发挥作用，调节数百个基因——许多基因以组织特异性的方式发挥作用。p53 DNA 结合和四聚化结构域中的癌症错义突变证实了这些结构域在肿瘤抑制中的重要性。具有功能性四聚化结构域的 p53 突变体形成混合四聚体，在某些情况下具有显性负效应（DNE），使野生型 p53 失活。DNA 损伤似乎是必需的，但不是充分的 DNE，表明上游信号影响 DNE。翻译后修饰和蛋白质-蛋白质相互作用改变了 p53 的四聚化，影响转录、稳定性和定位。这些调节成分限制了突变型 p53 对野生型 p53 活性的显性负效应。对 DNE 的分子基础有更深入的了解可能会推动开发释放 WT p53 并允许肿瘤抑制的药物。
