title: Recruitment of RPL11 at promoter sites of p53-regulated genes upon nucleolar stress through NEDD8 and in an Mdm2-dependent manner.
abstract: Ribosomal proteins (RPs) activate the p53 tumour-suppressor protein upon disruption of the nucleolus. However, the exact mechanisms for p53 transcriptional activation through RPs are not well understood. We show that the RPL11 is rapidly but transiently recruited at promoter sites of p53-regulated genes upon nucleolar stress induced by actinomycin D (ActD). Characterisation of molecular events at p53 promoter sites shows that L11 is required for the recruitment of p53 transcriptional co-activators p300/CBP and p53 K382 acetylation. We found that direct binding to Mdm2 E3 ligase and NEDDylation of L11 are critical regulators for L11 promoter recruitment. Our data suggest that binding of L11 to Mdm2 at the promoter results in relief from Mdm2-mediated transcriptional repression of p53. Analysis of chromatin and RNA polymerase II markers suggests that L11 is involved in the initiation step of transcriptional activation. Furthermore, analysis of 36 ActD-induced genes shows that L11 and NEDD8 are global regulators of the p53 activation response. The studies provide insights on how nucleolar stress through L11 and NEDD8 can activate the transcriptional activity of p53.
authors.affiliation: Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, Scotland.
authors.forename: B
authors.initials: B
authors.lastname: Mahata
authors.forename: A
authors.initials: A
authors.lastname: Sundqvist
authors.forename: D P
authors.initials: DP
authors.lastname: Xirodimas
mesh_terms: D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism; D002843:Chromatin; D006801:Humans; D009154:Mutation; D000075687:NEDD8 Protein; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012341:RNA, Ribosomal, 5S / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D002843:Chromatin; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D012341:RNA, Ribosomal, 5S; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C027624:ribosomal protein L11; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2