title: YB-1 is important for late-stage embryonic development, optimal cellular stress responses, and the prevention of premature senescence.
abstract: Proteins containing "cold shock" domains belong to the most evolutionarily conserved family of nucleic acid-binding proteins known among bacteria, plants, and animals. One of these proteins, YB-1, is widely expressed throughout development and has been implicated as a cell survival factor that regulates the transcription and/or translation of many cellular growth and death-related genes. For these reasons, YB-1 deficiency has been predicted to be incompatible with cell survival. However, the majority of YB-1(-/-) embryos develop normally up to embryonic day 13.5 (E13.5). After E13.5, YB-1(-/-) embryos exhibit severe growth retardation and progressive mortality, revealing a nonredundant role of YB-1 in late embryonic development. Fibroblasts derived from YB-1(-/-) embryos displayed a normal rate of protein synthesis and minimal alterations in the transcriptome and proteome but demonstrated reduced abilities to respond to oxidative, genotoxic, and oncogene-induced stresses. YB-1(-/-) cells under oxidative stress expressed high levels of the G(1)-specific CDK inhibitors p16Ink4a and p21Cip1 and senesced prematurely; this defect was corrected by knocking down CDK inhibitor levels with specific small interfering RNAs. These data suggest that YB-1 normally represses the transcription of CDK inhibitors, making it an important component of the cellular stress response signaling pathway.
authors.affiliation: Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Zhi Hong
authors.initials: ZH
authors.lastname: Lu
authors.forename: Jason T
authors.initials: JT
authors.lastname: Books
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Ley
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000166:cytology; D047108:Embryonic Development; D005317:Fetal Growth Retardation / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D018390:Gene Targeting; D005804:Genes, Lethal; D051379:Mice; D018384:Oxidative Stress; D014176:Protein Biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics; D014157:Transcription Factors
chemical_list: D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; C493957:Cdkn1a protein, mouse; C541744:Ybx1 protein, mouse; D014157:Transcription Factors