title: Ribosomal protein L4 is a novel regulator of the MDM2-p53 loop.
abstract: A number of ribosomal proteins (RPs) have been shown to play a critical role in coordinating ribosome biogenesis with cell growth and proliferation by suppressing MDM2 to induce p53 activation. While how the MDM2-p53 pathway is regulated by multiple RPs is unclear, it remains to be interesting to identify additional RPs that can regulate this pathway. Here we report that ribosomal protein L4 (RPL4) directly interacts with MDM2 at the central acidic domain and suppresses MDM2-mediated p53 ubiquitination and degradation, leading to p53 stabilization and activation. Interestingly, overexpression of RPL4 promotes the binding of MDM2 to RPL5 and RPL11 and forms a complex with RPL5, RPL11 and MDM2 in cells. Conversely, knockdown of RPL4 also induces p53 levels and p53-dependent cell cycle arrest. This p53-dependent effect requires both RPL5 and RPL11, suggesting that depletion of RPL4 triggers ribosomal stress. Together, our results reveal that balanced levels of RPL4 are critical for normal cell growth and proliferation via regulating the MDM2-p53 loop.
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine and The OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.|Department of Radiation Oncology, Jiangsu Cancer Hospital, Nanjing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine and The OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Yuhuang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine and The OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Mu-Shui
authors.initials: MS
authors.lastname: Dai
authors.affiliation: Department of Molecular and Medical Genetics, School of Medicine and The OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Sun
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology*; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C056368:ribosomal protein L4; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; RPL4; p53; ribosome proteins; ubiquitination