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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Cell Cycle
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dactinomycin / pharmacology
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Gene Knockdown Techniques
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HeLa Cells
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Humans
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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Protein Precursors / genetics
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Protein Precursors / metabolism
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Protein Structure, Tertiary
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Ribosomal Proteins / genetics
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Ribosomal Proteins / metabolism*
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Signal Transduction*
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Stress, Physiological*
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Trans-Activators
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitination / drug effects
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Ubiquitination / genetics
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Ubiquitins / genetics
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Ubiquitins / metabolism
Substances
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DNA-Binding Proteins
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MAML2 protein, human
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Nuclear Proteins
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Nucleic Acid Synthesis Inhibitors
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Protein Precursors
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Ribosomal Proteins
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TP53 protein, human
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Protein p53
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Ubiquitins
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ribosomal protein S27a
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ubiquitin precursor
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Dactinomycin
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Proteasome Endopeptidase Complex