Induction of Cullin 7 by DNA damage attenuates p53 function
Induction of Cullin 7 by DNA damage attenuates p53 function
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DOI：
10.1073/pnas.0609467104
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发表时间：
2007-07-03
影响因子：
11.1
通讯作者：
Hermeking, Heiko
中科院分区：
文献类型：
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作者：
Jung, Peter;Verdoodt, Berlinda;Hermeking, Heiko
p53抑癌基因编码一种转录因子，在DNA损伤后被激活。在p53 interactors的蛋白质筛选中，我们发现cullin蛋白Cu 17有效地与p53结合。DNA损伤后，CUP蛋白水平以咖啡因敏感但不依赖于p53的方式增加。通过条件性microRNA表达下调Cu 17增强了p53介导的对细胞周期进程的抑制。Cu 17的异位表达抑制了DNA损伤剂对p53的激活，并使细胞对阿霉素敏感。尽管CuP将F-box蛋白FBX 29募集到p53，但Cul 7/FBX 29的联合表达在体内并不促进p53的泛素化和降解。因此，推测Cu 17对p53活性的抑制是通过替代机制介导的。p53和Cu 17之间的相互作用类似于针对p53和Mdm 2描述的负反馈回路。Cu 17功能的药理学调节可能允许表达野生型p53的癌细胞对癌症治疗中使用的遗传毒性剂敏感。
The p53 tumor suppressor gene encodes a transcription factor, which is translationally and posttranslationally activated after DNA damage. In a proteornic screen for p53 interactors, we found that the cullin protein Cu17 efficiently associates with p53. After DNA damage, the level of CUP protein increased in a caffeinesensitive, but p53-independent, manner. Down-regulation of Cu17 by conditional microRNA expression augmented p53-mediated inhibition of cell cycle progression. Ectopic expression of Cu17 inhibited activation of p53 by DNA damaging agents and sensitized cells to adriamycin. Although CuP recruited the F-box protein FBX29 to p53, the combined expression of Cul7/FBX29 did not promote ubiquitination and degradation of p53 in vivo. Therefore, the inhibition of p53 activity by Cu17 is presumably mediated by alternative mechanisms. The interplay between p53 and Cu17 resembles the negative feedback loop described for p53 and Mdm2. Pharmacological modulation of Cu17 function may allow the sensitization of cancer cells expressing wild-type p53 to genotoxic agents used in cancer therapy.