title: Ribosomal proteins RPL37, RPS15 and RPS20 regulate the Mdm2-p53-MdmX network.
abstract: Changes to the nucleolus, the site of ribosome production, have long been linked to cancer, and mutations in several ribosomal proteins (RPs) have been associated with an increased risk for cancer in human diseases. Relevantly, a number of RPs have been shown to bind to MDM2 and inhibit MDM2 E3 ligase activity, leading to p53 stabilization and cell cycle arrest, thus revealing a RP-Mdm2-p53 signaling pathway that is critical for ribosome biogenesis surveillance. Here, we have identified RPL37, RPS15, and RPS20 as RPs that can also bind Mdm2 and activate p53. We found that each of the aforementioned RPs, when ectopically expressed, can stabilize both co-expressed Flag-tagged Mdm2 and HA-tagged p53 in p53-null cells as well as endogenous p53 in a p53-containing cell line. For each RP, the mechanism of Mdm2 and p53 stabilization appears to be through inhibiting the E3 ubiquitin ligase activity of Mdm2. Interestingly, although they are each capable of inducing cell death and cell cycle arrest, these RPs differ in the p53 target genes that are regulated upon their respective introduction into cells. Furthermore, each RP can downregulate MdmX levels but in distinct ways. Thus, RPL37, RPS15 and RPS20 regulate the Mdm2-p53-MdmX network but employ different mechanisms to do so.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, New York, United States of America.
authors.forename: Lilyn
authors.initials: L
authors.lastname: Daftuar
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xavier
authors.initials: X
authors.lastname: Jacq
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D002453:Cell Cycle; D045744:Cell Line, Tumor; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: C488984:RPL37 protein, human; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C029611:ribosomal protein S20; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2