Abstract
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.
Highlights
The nucleolus is a sub-nuclear compartment that assembles around tandem-repeat ribosomal DNA clusters[1]
To determine whether Cellular senescence-inhibited gene (CSIG) is involved in the nucleolar stress response, we first examined the localization of CSIG under nucleolar stress triggered by actinomycin D (ActD), Dox or knockdown of transcription initiation factor-IA (TIF-IA) by using short interfering RNA
L1 functions both as a ribosomal protein that binds rRNA and as a translational repressor that binds its own mRNA37. This evidence, together with the observation that suppressing rRNA gene transcription induces the translocation of CSIG from the nucleolus (Fig. 1), suggests that CSIG may be anchored to the nucleolus through rRNA
Summary
The nucleolus is a sub-nuclear compartment that assembles around tandem-repeat ribosomal DNA clusters[1]. The nucleolus is primarily associated with ribosome biogenesis, recent evidence has shown that it serves an additional function as a cellular stress sensor in the regulation of the stress response[2]. Mouse double minute 2 (MDM2), an E3 ubiquitin ligase, has been identified as a crucial negative regulator of p53 that inhibits p53’s transcriptional activity and promotes its ubiquitination and degradation[7,8,9,10]. In response to nucleolar stress, several nucleolar proteins, including RPL517, RPL1118,19, RPL2320,21, RPL2622, RPL623, RPS724, RPS1425, nucleolin (C23)[26], nucleophosmin (NPM/B23)[27], alternative reading frame (ARF)[28], and nucleostemin (NS)[29], are released into the nucleoplasm, where they bind to MDM2 and inhibit its E3 ubiquitin ligase function, leading to p53 stabilization and activation. Whether CSIG is involved in the nucleolar stress response remains unknown
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