title: RACK1 depletion in a mouse model causes lethality, pigmentation deficits and reduction in protein synthesis efficiency.
abstract: The receptor for activated C-kinase 1 (RACK1) is a conserved structural protein of 40S ribosomes. Strikingly, deletion of RACK1 in yeast homolog Asc1 is not lethal. Mammalian RACK1 also interacts with many nonribosomal proteins, hinting at several extraribosomal functions. A knockout mouse for RACK1 has not previously been described. We produced the first RACK1 mutant mouse, in which both alleles of RACK1 gene are defective in RACK1 expression (ΔF/ΔF), in a pure C57 Black/6 background. In a sample of 287 pups, we observed no ΔF/ΔF mice (72 expected). Dissection and genotyping of embryos at various stages showed that lethality occurs at gastrulation. Heterozygotes (ΔF/+) have skin pigmentation defects with a white belly spot and hypopigmented tail and paws. ΔF/+ have a transient growth deficit (shown by measuring pup size at P11). The pigmentation deficit is partly reverted by p53 deletion, whereas the lethality is not. ΔF/+ livers have mild accumulation of inactive 80S ribosomal subunits by polysomal profile analysis. In ΔF/+ fibroblasts, protein synthesis response to extracellular and pharmacological stimuli is reduced. These results highlight the role of RACK1 as a ribosomal protein converging signaling to the translational apparatus.
authors.affiliation: Laboratory of Molecular Histology and Cell Growth, Division of Oncology, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Volta
authors.forename: Anne
authors.initials: A
authors.lastname: Beugnet
authors.forename: Simone
authors.initials: S
authors.lastname: Gallo
authors.forename: Laura
authors.initials: L
authors.lastname: Magri
authors.forename: Daniela
authors.initials: D
authors.lastname: Brina
authors.forename: Elisa
authors.initials: E
authors.lastname: Pesce
authors.forename: Piera
authors.initials: P
authors.lastname: Calamita
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Stefano
authors.initials: S
authors.lastname: Biffo
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020964:Embryo Loss / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism / Q000648:ultrastructure; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010858:Pigmentation; D014176:Protein Biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000075370:Receptors for Activated C Kinase; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D009479:Neuropeptides; C090294:RACK1 protein, mouse; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D016159:Tumor Suppressor Protein p53