Department of Pediatrics (Division of Hematology/Oncology), Indianapolis, IN 46202, USA.
Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Int J Mol Sci. 2017 Oct 23;18(10):2216. doi: 10.3390/ijms18102216.
In cancer, the mouse double minute 2 (MDM2) is an oncoprotein that contributes to the promotion of cell growth, survival, invasion, and therapeutic resistance. The impact of MDM2 on cell survival versus cell death is complex and dependent on levels of MDM2 isoforms, p53 status, and cellular context. Extensive investigations have demonstrated that MDM2 protein-protein interactions with p53 and other p53 family members (p63 and p73) block their ability to function as transcription factors that regulate cell growth and survival. Upon genotoxic insults, a dynamic and intricately regulated DNA damage response circuitry is activated leading to release of p53 from MDM2 and activation of cell cycle arrest. What ensues following DNA damage, depends on the extent of DNA damage and if the cell has sufficient DNA repair capacity. The well-known auto-regulatory loop between p53-MDM2 provides an additional layer of control as the cell either repairs DNA damage and survives (i.e., MDM2 re-engages with p53), or undergoes cell death (i.e., MDM2 does not re-engage p53). Furthermore, the decision to live or die is also influenced by chromatin-localized MDM2 which directly interacts with the Mre11-Rad50-Nbs1 complex and inhibits DNA damage-sensing giving rise to the potential for increased genome instability and cellular transformation.
在癌症中，双微体 2（MDM2）是一种癌蛋白，有助于促进细胞生长、存活、侵袭和治疗耐药性。MDM2 对细胞存活与细胞死亡的影响很复杂，取决于 MDM2 同工型的水平、p53 状态和细胞环境。大量研究表明，MDM2 蛋白与 p53 和其他 p53 家族成员（p63 和 p73）的蛋白-蛋白相互作用会阻止它们作为转录因子发挥作用，从而调节细胞生长和存活。在遗传毒性损伤后，一个动态且错综复杂的 DNA 损伤反应电路被激活，导致 p53 从 MDM2 中释放出来，并激活细胞周期停滞。DNA 损伤后会发生什么，取决于 DNA 损伤的程度以及细胞是否具有足够的 DNA 修复能力。p53-MDM2 之间众所周知的自动调节环提供了一个额外的控制层，因为细胞要么修复 DNA 损伤并存活（即 MDM2 重新与 p53 结合），要么发生细胞死亡（即 MDM2 不会重新与 p53 结合）。此外，生死抉择还受到染色质定位的 MDM2 的影响，它直接与 Mre11-Rad50-Nbs1 复合物相互作用，抑制 DNA 损伤感应，从而增加基因组不稳定性和细胞转化的可能性。
Zotero 插件
