title: Interplay between ribosomal protein S27a and MDM2 protein in p53 activation in response to ribosomal stress.
abstract: Ribosomal proteins play a critical role in tightly coordinating p53 signaling with ribosomal biogenesis. Several ribosomal proteins have been shown to induce and activate p53 via inhibition of MDM2. Here, we report that S27a, a small subunit ribosomal protein synthesized as an 80-amino acid ubiquitin C-terminal extension protein (CEP80), functions as a novel regulator of the MDM2-p53 loop. S27a interacts with MDM2 at the central acidic domain of MDM2 and suppresses MDM2-mediated p53 ubiquitination, leading to p53 activation and cell cycle arrest. Knockdown of S27a significantly attenuates the p53 activation in cells in response to treatment with ribosomal stress-inducing agent actinomycin D or 5-fluorouracil. Interestingly, MDM2 in turn ubiquitinates S27a and promotes proteasomal degradation of S27a in response to actinomycin D treatment, thus forming a mutual-regulatory loop. Altogether, our results reveal that S27a plays a non-redundant role in mediating p53 activation in response to ribosomal stress via interplaying with MDM2.
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine and the OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Sun
authors.forename: Tiffany
authors.initials: T
authors.lastname: DeVine
authors.forename: Kishore B
authors.initials: KB
authors.lastname: Challagundla
authors.forename: Mu-Shui
authors.initials: MS
authors.lastname: Dai
mesh_terms: D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C471297:MAML2 protein, human; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011498:Protein Precursors; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C096227:ribosomal protein S27a; C045677:ubiquitin precursor; D003609:Dactinomycin; D046988:Proteasome Endopeptidase Complex