Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors
Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors
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DOI：
10.4161/cc.20208
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发表时间：
2012-05-01
期刊：
影响因子：
4.3
通讯作者：
Eastman, Alan
中科院分区：
文献类型：
--
作者：
Chang, Li-Ju;Eastman, Alan
DNA损伤通过Chk 1和p53肿瘤抑制蛋白诱导细胞周期阻滞，后者通过诱导p21（waf 1）蛋白阻滞细胞。细胞停滞可以修复损伤并恢复。肿瘤细胞中p53的频繁丢失使它们更依赖于Chk 1的抑制和存活。然而，一些p53野生型肿瘤细胞系，如HCT 116和U2 OS，由于DNA损伤后p21（waf 1）诱导减弱，也对Chk 1的抑制敏感。本研究的目的是确定这种减弱的p21（waf 1）蛋白诱导的原因。我们发现p21（waf 1）mRNA的诱导和蛋白半衰期都不足以解释HCT 116和U2 OS细胞中p21（waf 1）蛋白水平低的原因。诱导的mRNA与多核糖体结合，但很少产生蛋白质，表明这两种细胞系具有降低的p21（waf 1）mRNA翻译速率。这代表了破坏p53-p21（waf 1）通路的一种新机制，因为目前已知的机制涉及p53突变或p53蛋白水平降低。因此，这种减弱的p21（waf 1）表达可能使一些p53野生型肿瘤对DNA损伤和检查点抑制的组合敏感。
DNA damage induces cell cycle arrest through both Chk1 and the p53 tumor suppressor protein, the latter arresting cells through induction of p21(waf1) protein. Arrest permits cells to repair the damage and recover. The frequent loss of p53 in tumor cells makes them more dependent on Chk1 for arrest and survival. However, some p53 wild-type tumor cell lines, such as HCT116 and U2OS, are also sensitive to inhibition of Chk1 due to attenuated p21(waf1) induction upon DNA damage. The purpose of this study is to determine the cause of this attenuated p21(waf1) protein induction. We find that neither the induction of p21(waf1) mRNA nor protein half-life is sufficient to explain the low p21(waf1) protein levels in HCT116 and U2OS cells. The induced mRNA associates with polysomes, but little protein is made, suggesting that these two cell lines have a reduced rate of p21(waf1) mRNA translation. This represents a novel mechanism for disruption of the p53-p21(waf1) pathway, as currently known mechanisms involve either mutation of p53 or reduction of p53 protein levels. As a consequence, this attenuated p21(waf1) expression may render some p53 wild-type tumors sensitive to a combination of DNA damage plus checkpoint inhibition.