Carr Michael I, Jones Stephen N
Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Transl Cancer Res. 2016 Dec;5(6):707-724. doi: 10.21037/tcr.2016.11.75.
The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function. Although regulation of p53 levels and function is coordinated by many proteins, it is now widely accepted that the master regulator of p53 is Mdm2. In this review, we discuss the role(s) of p53 in the DNA damage response and in tumor suppression, and how post-translational modification of Mdm2 regulates the Mdm2-p53 signaling axis to govern p53 activities in the cell.
p53肿瘤抑制因子在遭受各种形式细胞应激（包括不适当的生长信号或电离辐射）诱导DNA双链断裂的哺乳动物细胞中，充当基因组的守护者。损伤后，p53蛋白水平在细胞中大幅升高，且p53主要作为转录因子发挥作用，以调控多种协调这种DNA损伤反应的基因的表达。在遭受大量DNA损伤的细胞中，p53可促进细胞凋亡，而在损伤较轻的细胞中，p53则促进细胞衰老或短暂的细胞生长停滞以及参与DNA修复的基因的表达，这取决于细胞类型和损伤程度。受损细胞未能经历生长停滞或凋亡，或未能通过其他p53协调的机制对DNA损伤作出反应，可导致细胞生长不当和肿瘤发生。在成功应对基因损伤的细胞中，细胞内的p53含量必须恢复到基础水平，以便细胞恢复正常生长和功能。尽管p53水平和功能的调控由许多蛋白质协调，但现在人们普遍认为p53的主要调节因子是Mdm2。在本综述中，我们讨论了p53在DNA损伤反应和肿瘤抑制中的作用，以及Mdm2的翻译后修饰如何调节Mdm2-p⁵³信号轴以控制细胞中的p53活性。
