title: Nucleophosmin sets a threshold for p53 response to UV radiation.
abstract: Because activation of p53 can trigger cell cycle arrest and apoptosis, it is necessary for a cell to suppress this activation until it is absolutely required for survival. The mechanisms underlying this important regulatory event are poorly understood. Here we show that nucleophosmin (NPM) acts as a natural repressor of p53 by setting a threshold for p53 activation in response to UV radiation. NPM binds to the p53 N terminus and inhibits p53 transcriptional activity by more than 70%. Our data indicate that the levels of NPM in a cell determine the UV dose at which the tumor suppressor p53 can be phosphorylated on Ser15. Moreover, we show that NPM is a substrate for the UV-activated protein kinase ATR and inhibits the UV-induced p53 phosphorylation at Ser15. In addition, NPM forms a complex with p53 and ATR in vivo. These data suggest that NPM is an early responder to DNA damage that prevents premature activation of p53. In normal cells, NPM could contribute to suppressing p53 activation until its functions are absolutely required while in cancer cells overexpression of NPM could contribute to p53 inactivation and tumor progression.
authors.affiliation: Biochemistry and Molecular Biology Department, School of Medicine, and Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201-1503, USA.
authors.forename: Dony A
authors.initials: DA
authors.lastname: Maiguel
authors.forename: Leslie
authors.initials: L
authors.lastname: Jones
authors.forename: Devulapalli
authors.initials: D
authors.lastname: Chakravarty
authors.forename: Chonglin
authors.initials: C
authors.lastname: Yang
authors.forename: France
authors.initials: F
authors.lastname: Carrier
mesh_terms: D045744:Cell Line, Tumor; D002466:Cell Nucleolus; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000528:radiation effects*; D017930:Genes, Reporter; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D000090243:Nucleophosmin; D012694:Serine