title: hCINAP is a novel regulator of ribosomal protein-HDM2-p53 pathway by controlling NEDDylation of ribosomal protein S14.
abstract: The tumor-suppressor p53 provides a critical brake on tumor development. HDM2 (human double-minute 2), a p53 E3 ubiquitin ligase, is the principal cellular antagonist of p53. Mounting evidence has suggested that ribosomal proteins (RPs) modulate HDM2-p53 as a novel pathway for regulating p53 signaling. However, the upstream regulators that mediate RP-HDM2-p53 circuits remain poorly understood. Here we identify human coilin-interacting nuclear ATPase protein (hCINAP) as an interacting partner of ribosomal protein S14 (RPS14). RPS14 stabilized and activated p53 by inhibiting HDM2-mediated p53 polyubiquitination and degradation. More importantly, RPS14 was specifically modified with NEDD8 and hCINAP inhibited RPS14 NEDDylation by recruiting NEDD8-specific protease 1. The decrease in RPS14 NEDDylation led to reduced stability and incorrect localization of RPS14, thereby attenuating the interaction between RPS14 and HDM2. Free HDM2 stimulated p53 polyubiquitination and degradation. In conclusion, we demonstrate that hCINAP acts as a novel regulator of RPS14-HDM2-p53 by regulating the interaction between RPS14 and HDM2 through the control of RPS14 NEDDylation. These findings suggest that hCINAP is an important regulator of RP-HDM2-p53 pathway and a potential anticancer drug target.
authors.affiliation: 1] State Key Lab of Protein and Plant Gene Research, Beijing, China [2] Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] State Key Lab of Protein and Plant Gene Research, Beijing, China [2] Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
authors.forename: D
authors.initials: D
authors.lastname: Bai
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Ma
authors.affiliation: 1] State Key Lab of Protein and Plant Gene Research, Beijing, China [2] Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Guan
authors.affiliation: 1] State Key Lab of Protein and Plant Gene Research, Beijing, China [2] Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
mesh_terms: D004268:DNA-Binding Proteins; D010450:Endopeptidases / Q000502:physiology; D045325:HCT116 Cells; D006801:Humans; D000075687:NEDD8 Protein; D009687:Nuclear Proteins / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009687:Nuclear Proteins; C526722:RPS14 protein, human; D012269:Ribosomal Proteins; C495901:TP53 protein, human; C432963:TSPYL2 protein, human; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; C477008:SENP8 protein, human