title: Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage.
abstract: Upon DNA damage, tumor suppressor p53 determines cell fate by repairing DNA lesions to survive or by inducing apoptosis to eliminate damaged cells. The decision is based on its posttranslational modifications. Especially, p53 phosphorylation at Ser46 exerts apoptotic cell death. However, little is known about the precise mechanism of p53 phosphorylation on the induction of apoptosis. Here, we show that amphiregulin (AREG) is identified for a direct target of Ser46 phosphorylation via the comprehensive expression analyses. Ser46-phosphorylated p53 selectively binds to the promoter region of AREG gene, indicating that the p53 modification changes target genes by altering its binding affinity to the promoter. Although AREG belongs to a family of the epidermal growth factor, it also emerges in the nucleus under DNA damage. To clarify nuclear function of AREG, we analyze AREG-binding proteins by mass spectrometry. AREG interacts with DEAD-box RNA helicase p68 (DDX5). Intriguingly, AREG regulates precursor microRNA processing (i.e., miR-15a) with DDX5 to reduce the expression of antiapoptotic protein Bcl-2. These findings collectively support a mechanism in which the induction of AREG by Ser46-phosphorylated p53 is required for the microRNA biogenesis in the apoptotic response to DNA damage.
authors.affiliation: Department of Biochemistry, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Naoe
authors.initials: N
authors.lastname: Taira
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Junko
authors.initials: J
authors.lastname: Kimura
authors.forename: Zheng-Guang
authors.initials: ZG
authors.lastname: Lu
authors.forename: Shinji
authors.initials: S
authors.lastname: Fukuda
authors.forename: Shigeki
authors.initials: S
authors.lastname: Higashiyama
authors.forename: Masaya
authors.initials: M
authors.lastname: Ono
authors.forename: Kiyotsugu
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D066258:Amphiregulin; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D066255:EGF Family of Proteins; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D013058:Mass Spectrometry; D035683:MicroRNAs / Q000096:biosynthesis*; D046228:Microarray Analysis; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; C506749:Ddx5 protein, human; D053487:DEAD-box RNA Helicases
keywords: Drosha; miRNA processing; microarray