title: Mutual protection of ribosomal proteins L5 and L11 from degradation is essential for p53 activation upon ribosomal biogenesis stress.
abstract: Impairment of ribosomal biogenesis can activate the p53 protein independently of DNA damage. The ability of ribosomal proteins L5, L11, L23, L26, or S7 to bind Mdm2 and inhibit its ubiquitin ligase activity has been suggested as a critical step in p53 activation under these conditions. Here, we report that L5 and L11 are particularly important for this response. Whereas several other newly synthesized ribosomal proteins are degraded by proteasomes upon inhibition of Pol I activity by actinomycin D, L5 and L11 accumulate in the ribosome-free fraction where they bind to Mdm2. This selective accumulation of free L5 and L11 is due to their mutual protection from proteasomal degradation. Furthermore, the endogenous, newly synthesized L5 and L11 continue to be imported into nucleoli even after nucleolar disruption and colocalize with Mdm2, p53, and promyelocytic leukemia protein. This suggests that the disrupted nucleoli may provide a platform for L5- and L11-dependent p53 activation, implying a role for the nucleolus in p53 activation by ribosomal biogenesis stress. These findings may have important implications with respect to understanding the pathogenesis of diseases caused by impaired ribosome biogenesis.
authors.affiliation: Department of Molecular Medicine and Biotechnology, School of Medicine,  University of Rijeka, 51000 Rijeka,  Croatia.
authors.forename: Sladana
authors.initials: S
authors.lastname: Bursać
authors.forename: Maja Cokarić
authors.initials: MC
authors.lastname: Brdovčak
authors.forename: Martin
authors.initials: M
authors.lastname: Pfannkuchen
authors.forename: Ines
authors.initials: I
authors.lastname: Orsolić
authors.forename: Lior
authors.initials: L
authors.lastname: Golomb
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Chen
authors.initials: C
authors.lastname: Katz
authors.forename: Lilyn
authors.initials: L
authors.lastname: Daftuar
authors.forename: Kristina
authors.initials: K
authors.lastname: Grabušić
authors.forename: Iva
authors.initials: I
authors.lastname: Vukelić
authors.forename: Vedrana
authors.initials: V
authors.lastname: Filić
authors.forename: Moshe
authors.initials: M
authors.lastname: Oren
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.forename: Siniša
authors.initials: S
authors.lastname: Volarevic
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C027624:ribosomal protein L11; C549166:ribosomal protein L5, human; C070576:PML protein, human; D003609:Dactinomycin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex