title: Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models.
abstract: Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background. A detailed examination of the bone marrow in these mice identified reduced numbers of haematopoietic stem cells and a p53-dependent c-Kit down-regulation. These studies suggest that reduced Rpl27a increases p53 activity in vivo, further evident with a delay in tumorigenesis in mutant mice. Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation.
authors.affiliation: Department of Dermatology, UC Denver, Aurora, CO, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Terzian
authors.forename: Melissa
authors.initials: M
authors.lastname: Dumble
authors.forename: Farinaz
authors.initials: F
authors.lastname: Arbab
authors.forename: Christina
authors.initials: C
authors.lastname: Thaller
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Donehower
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
authors.forename: Neil F
authors.initials: NF
authors.lastname: Box
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006130:Growth Disorders / Q000235:genetics / Q000378:metabolism; D057895:Haploinsufficiency / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000473:pathology; D017495:Hyperpigmentation / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009152:Mutagenicity Tests; D010641:Phenotype; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D012269:Ribosomal Proteins; C486161:Rpl27a protein, mouse; D016159:Tumor Suppressor Protein p53