Division of Viral Transformation Mechanisms, Research Program Infection, Inflammation & Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany.
Int J Mol Sci. 2020 Dec 15;21(24):9533. doi: 10.3390/ijms21249533.
Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., and ) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., and ) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral -oncogenes as drivers for proliferation remained inhibited under hypoxia.
尽管人们对 HPV 阳性癌细胞中缺氧对 p53 的影响进行了数十年的研究，但在缺氧的不同时期，p53 调节对下游靶标和细胞适应过程的影响仍不清楚。在这里，我们表明，尽管 HPV16 致癌基因持续受到抑制，p53 并没有立即恢复，而是在 24 小时内进一步耗竭后出现双相调节，然后在 72 小时增加。值得注意的是，在 致癌基因抑制期间，溶酶体降解拮抗 p53 的重建。因此，与衰老相关的 p53 反应基因（例如， 和 ）的转录不能被上调。相比之下，参与自噬的下游基因（例如， 和 ）被激活，从而在缺氧条件下逃避衰老。因此，p53 及其下游反应基因网络的动态调节有利于细胞适应并增强细胞存活，尽管作为增殖驱动因素的病毒 -致癌基因的表达在缺氧下仍然受到抑制。
