Induction of Cullin 7 by DNA damage attenuates p53 function

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.