title: Physical and functional interaction between ribosomal protein L11 and the tumor suppressor ARF.
abstract: The ARF tumor suppressor protein activates p53 in response to oncogenic stress, whereas ribosomal protein L11 induces p53 following ribosomal stress. Both proteins bind to central, albeit non-overlapping, regions of MDM2 and suppress MDM2 activity toward p53. However, it is not known whether the two pathways are functionally connected. Here we show that ARF directly binds to L11 in vitro and in cells, which then forms a complex with MDM2 and p53. L11 collaboratively enhances ARF-induced p53 transcriptional activity and cell cycle arrest. Supporting these results, knocking down L11 reduces ARF-mediated p53 accumulation and alleviates ARF-induced cell cycle arrest. Interestingly, overexpression of ARF increases the levels of ribosome-free L11 and enhances the interaction of L11 with MDM2 and p53. These results demonstrate that ARF activates p53, at least partly by induction of ribosomal stress, which results in L11 suppression of MDM2, and suggest that the ARF-MDM2-p53 and the L11-MDM2-p53 pathways are functionally connected.
authors.affiliation: Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Departments of Molecular and Medical Genetics, School of Medicine, and the OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Mu-Shui
authors.initials: MS
authors.lastname: Dai
authors.affiliation: Departments of Molecular and Medical Genetics, School of Medicine, and the OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Kishore B
authors.initials: KB
authors.lastname: Challagundla
authors.affiliation: Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Departments of Molecular and Medical Genetics, School of Medicine, and the OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Lakshmi Reddy
authors.initials: LR
authors.lastname: Palam
authors.affiliation: Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
authors.forename: Shelya X
authors.initials: SX
authors.lastname: Zeng
authors.affiliation: Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Wek
authors.affiliation: Department of Biochemistry and Molecular Biology and Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112. Electronic address: hlu2@tulane.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
mesh_terms: D059447:Cell Cycle Checkpoints / Q000502:physiology*; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000096:biosynthesis* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2