...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Molecular and Cellular Biology >How Many Mutant p53 Molecules Are Needed To Inactivate a Tetramer?
【24h】

How Many Mutant p53 Molecules Are Needed To Inactivate a Tetramer?

机译：要使四聚体失活，需要多少突变的p53分子？

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The tumor suppressor p53 is transcription factor composed of four identical subunits. The majority of the mutations in p53 are missense mutations that impair DNA binding. On the other hand, the p53-related p63 and p73 genes are rarely mutated, but many cell types express natural variants lacking the N-terminal transactivation domain (NΔ). Compelling evidence indicates that both the DNA binding-defective and NΔ mutants can impair the function of wild-type p53 in a dominant-negative manner. Interestingly, it is uncertain how many mutant subunit(s) a p53 tetramer can tolerate. In this study, we first made theoretical predictions based on the number of mutant p53 monomers needed to inactivate a tetramer and then tested how well the experimental data fit the predicted values. Surprisingly, these experiments reveal that DNA binding-defective p53 mutants (R249S and R273H) are very ineffective in impairing the transcriptional activity of p53: at least three mutants are required to inactivate a tetramer. In marked contrast, p53NΔ is a very potent inhibitor of p53: one NΔ subunit per tetramer is sufficient to abolish the transcriptional activity. DNA binding is not necessary for the NΔ proteins to inactivate p53. Similarly, NΔ variants of p63 and p73 are also powerful inhibitors of members of the p53 family. These results have important implications for our thinking about the mechanism of tumorigenesis involving missense p53 mutants or the N-terminally truncated isoforms.
机译：肿瘤抑制因子p53是由四个相同亚基组成的转录因子。 p53 中的大多数突变是会损害DNA结合的错义突变。另一方面，与 p53 相关的 p63 和 p73 基因很少发生突变，但是许多细胞类型表达缺乏N末端的天然变异体反式激活域（NΔ）。有力的证据表明，DNA结合缺陷型突变体和NΔ突变体均可以显性-阴性方式破坏野生型p53的功能。有趣的是，尚不确定p53四聚体可耐受多少个突变亚基。在这项研究中，我们首先根据灭活四聚体所需的突变p53单体的数量进行了理论预测，然后测试了实验数据与预测值的拟合程度。出乎意料的是，这些实验表明DNA结合缺陷型p53突变体（R249S和R273H）在削弱p53的转录活性方面非常无效：至少需要三个突变体才能使四聚体失活。与之形成鲜明对比的是，p53NΔ是p53的强效抑制剂：每个四聚体一个NΔ亚基足以消除转录活性。 DNA结合对于NΔ蛋白灭活p53并不是必需的。类似地，p63和p73的NΔ变体也是p53家族成员的有力抑制剂。这些结果对我们关于涉及错义p53突变体或N末端截短的亚型的肿瘤发生机理的思考具有重要意义。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号