Ribosomal protein S27-like and S27 interplay with p53-MDM2 axis s a target, a substrate, and a regulator

Several ribosomal proteins regulate p53 function via modulating MDM2. We recently found that RPS27L, a RPS27 like protein, is a direct p53 inducible target. Here we showed that RPS27 itself is a p53 repressible target. Furthermore, the N-terminal region of either RPS27L or RPS27 binds to MDM2 on the central acidic domain of MDM2. RPS27L or RPS27 forms an in vivo triplex with MDM2-p53 and competes with p53 for MDM2 binding. Like p53, RPS27L, but not RPS27, is a short-lived protein and a novel MDM2 substrate. Degradation of RPS27L requires the RING or acidic domain of MDM2. Ectopic expression of RPS27L or RPS27 inhibits MDM-2-mediated p53 ubiquitination and increases p53 levels by extending p53 protein half-life, whereas siRNA silencing of RPS27L decreases p53 levels by shortening p53 half-life with a corresponding reduction in p53 transcription activity. RPS27L is mainly localized in the cytoplasm, but upon p53-activating signals, a portion of RPS27L shuttled to the nucleoplasm where it co-localizes with MDM2. Both cytoplasmic and nuclear p53, induced by ribosomal stress, were reduced upon RPS27L silencing. Our study reveals a multi-level interplay among RPS27L/S27 and p53-MDM2 axis with RPS27L acting as a p53 target, an MDM2 substrate, and a p53 regulator.