title: Ribosomal Protein Mutations Result in Constitutive p53 Protein Degradation through Impairment of the AKT Pathway.
abstract: Mutations in ribosomal protein (RP) genes can result in the loss of erythrocyte progenitor cells and cause severe anemia. This is seen in patients with Diamond-Blackfan anemia (DBA), a pure red cell aplasia and bone marrow failure syndrome that is almost exclusively linked to RP gene haploinsufficiency. While the mechanisms underlying the cytopenia phenotype of patients with these mutations are not completely understood, it is believed that stabilization of the p53 tumor suppressor protein may induce apoptosis in the progenitor cells. In stark contrast, tumor cells from zebrafish with RP gene haploinsufficiency are unable to stabilize p53 even when exposed to acute DNA damage despite transcribing wild type p53 normally. In this work we demonstrate that p53 has a limited role in eliciting the anemia phenotype of zebrafish models of DBA. In fact, we find that RP-deficient embryos exhibit the same normal p53 transcription, absence of p53 protein, and impaired p53 response to DNA damage as RP haploinsufficient tumor cells. Recently we reported that RP mutations suppress activity of the AKT pathway, and we show here that this suppression results in proteasomal degradation of p53. By re-activating the AKT pathway or by inhibiting GSK-3, a downstream modifier that normally represses AKT signaling, we are able to restore the stabilization of p53. Our work indicates that the anemia phenotype of zebrafish models of DBA is dependent on factors other than p53, and may hold clinical significance for both DBA and the increasing number of cancers revealing spontaneous mutations in RP genes.
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Antunes
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Goos
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Tamara C
authors.initials: TC
authors.lastname: Pereboom
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Hermkens
authors.affiliation: Department of Pediatric Hematology and Oncology, University of Freiburg, Freiburg, Germany.
authors.forename: Marcin W
authors.initials: MW
authors.lastname: Wlodarski
authors.affiliation: AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Paris F-75019, France; Laboratoire d'excellence, GR-Ex, Paris, France; Université Paris VII-Denis Diderot, Sorbonne Paris Cité, Paris F-75475, France; U1149, CRB3, Paris, France.
authors.forename: Lydie
authors.initials: L
authors.lastname: Da Costa
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Alyson W
authors.initials: AW
authors.lastname: MacInnes
mesh_terms: D029503:Anemia, Diamond-Blackfan / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D057895:Haploinsufficiency / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D060172:Morpholinos / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D007976:Leupeptins; D060172:Morpholinos; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C571228:tp53 protein, zebrafish; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; D018021:Lithium Chloride; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde