Regulation of the MDM2-p53 pathway by the nucleolar protein CSIG in response to nucleolar stress

Nucleolar proteins play an important role in the regulation of the MDM2–p53 pathway, which coordinates cellular response to stress. However, the mechanism underlying this regulation remains poorly understood. Here, we report that the nucleolar protein CSIG is a novel and crucial regulator of the MDM2–p53 pathway. We demonstrate that CSIG translocates from the nucleolus to the nucleoplasm in response to nucleolar stress. Moreover, knockdown of CSIG attenuates the induction of p53 and abrogates G1 phase arrest in response to nucleolar stress. CSIG interacts directly with the MDM2 RING finger domain and inhibits MDM2 E3 ubiquitin ligase activity, thus resulting in a decrease in MDM2-mediated p53 ubiquitination and degradation. Our results suggest that the CSIG–MDM2–p53 regulatory pathway plays an important role in the cellular response to nucleolar stress.