MDM2 expression is repressed by the RNA-binding protein RNPC1 via mRNA stability.
The RNA-binding protein (RBP) RNPC1 is a target of the p53 family and forms a feedback regulatory loop with the p53 family proteins. The murine double minute-2 (MDM2) oncogene, a key negative regulator of p53, has a critical role in a variety of fundamental cellular processes. MDM2 expression is found to be regulated via gene amplification, transcription, protein translation and protein stability. In the current study, we reported a novel regulation of MDM2 by RNPC1 via mRNA stability. Specifically, we found that overexpression of RNPC1 decreases, whereas knockdown or knockout of RNPC1 increases, the level of MDM2 transcript and protein independent of p53. To uncover the underlying mechanism, we found that RNPC1 is able to destabilize the MDM2 transcript via binding to multiple AU-/U-rich elements in MDM2 3'untranslated region (3'UTR). Consistent with this, we showed that RNPC1 inhibits expression of exogenous MDM2 from an expression vector as long as the vector contains an AU-/U-rich element from MDM2 3'UTR. Finally, we showed that the RNA-binding activity of RNPC1 is required for binding to MDM2 transcript and consequently, for inhibiting MDM2 expression. Together, we uncover a novel regulation of MDM2 by the RBP RNPC1 via mRNA stability.
Comparative Oncology Laboratory, Department of Surgical and Radiological Sciences, University of California at Davis, Davis, CA 95616, USA.
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Zhang
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D020413:3' Untranslated Regions; D000818:Animals; D045744:Cell Line, Tumor; D015870:Gene Expression; D020868:Gene Silencing; D006207:Half-Life; D006801:Humans; D051379:Mice; D011485:Protein Binding; D020033:Protein Isoforms / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D020413:3' Untranslated Regions; D020033:Protein Isoforms; C515435:RBM38 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2